Re-establishing the comprehension of phytomedicine and nanomedicine in inflammation-mediated cancer signaling

to treat cancer. Researchers have identified multiple targets to specifically alter inflammation in cancer therapy


Introduction
Novel advancements in the treatment of cancer, which is a leading cause of morbidity and mortality worldwide, have resulted in modest impacts on patient survival.Determinants of cancer progression and survival are of increasing interest to researchers working to develop effective cancer therapies.Research in the recent decades has highlighted the importance of inflammatory responses in determining disease progression in patients with cancer [1].Studies support the impact of inflammation on every step of tumor development, including initiation, promotion, metastasis, and recurrence.Inflammation caused by autoimmune diseases, infections, and other factors that increase the risk of cancer and accelerate malignant progression, such as obesity, smoking, and alcohol consumption, termed as tumor-extrinsic and tumor-intrinsic inflammation, initiate mutations and provide a preferred background for tumor progression.The occurrence of genetic mutations increases in an inflamed microenvironment, promoting genetic instability, which further paves the way for cancer initiation [2].Inflammation regulates cancer development and may have antagonistic effects on therapeutic outcomes by facilitating resistance to treatment [3].Crosstalk between cancer cells and immune cells is either directly or indirectly through cytokine and chemokine signaling molecules.Pro-tumorigenic effects of inflammation, mediated by signaling pathways, often consist of feed forward loops.For instance, the cytokines produced by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in immune cells induce chemokines, which further results in an increased inflow of inflammatory cells into the tumor [4].In certain cases, therapy-induced inflammation may lead to immune-mediated tumor eradication to enhance antigen presentation.Thus, understanding the contribution of inflammation in various phases of tumor growth will assist in developing approaches to exploit the inflammatory pathways and selectively target the tumor-associated microenvironment for therapeutic and diagnostic purposes.
The pharmacological success of chemotherapeutics in cancer therapy is limited owing to a reduction in their efficacy due to degradation by specific enzymes and poor biodistribution, which increases extensive off-target effects [5].These effects are responsible for drug resistance and poor patient survival.With advancements in nanotechnology, we could expand the physicochemical features of chemotherapeutics, diminishing their overall toxicity while sustaining their pharmacological activities, and enhancing their therapeutic index and accretion at the disease site.A variety of nanomaterials have been utilized for the development and improvement of new cancer therapeutics.In this review, we will further discuss the role of nanoparticles (NPs) in cancer treatment by targeting different inflammatory signaling pathways for cancer therapy.

Revisiting inflammatory signaling in cancer
Inflammation is an evolutionarily conserved phenomenon that results in the activation of cells from both immune and non-immune compartments.The goal of the inflammatory process is to protect the host body from bacteria, viruses, toxins, and a multitude of infections, while simultaneously facilitating damaged tissue repair.Depending on the intensity and extent (systemic or local) of a particular immune response, several neuroendocrine and metabolic changes may occur in the host to channelize the energy and nutrient supply to the activated immune system.Although a sporadic rise in inflammation is critical for endurance during physical injury and infection, recent studies have demonstrated that specific social, environmental, and lifestyle factors can promote systemic chronic inflammation (SCI).SCI itself is detrimental to the body and can lead to diseases such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative disorders [6].In fact, SCI is a leading cause of disability and mortality in patients around the globe.
Regarding cancer, SCI promotes its initiation and progression by facilitating the development of a tumor-supportive microenvironment (Fig. 1).Furthermore, SCI triggers tumor progression by inducing the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are typically associated with DNA mutations.As chronic inflammation persists, mutations tend to accumulate, and some of these mutations can drive cell growth, survival, or even reduce cellular apoptosis [7].A key hallmark of chronic inflammatory conditions in the host body is the activation of inflammatory signaling pathways, such as Wnt/β-catenin, Janus-activated kinase (JAK)-signal transducers and activators 3 (STAT3), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/ mammalian target of rapamycin (PI3K/AKT/mTOR), NF-κB, mitogen-activated protein kinase (MAPK), and transforming growth factor (TGF)-β/Smad.Consequently, to prevent or limit SCI-induced tumor progression, it is imperative to understand the interaction between these signaling prototypes and their associated proteins at a molecular level.

NF-κB pathway
The transcription factor NF-κB is involved in the regulation of the innate immune system and inflammatory responses.NF-κB signaling can be either canonical or non-canonical.An inhibitor of NF-κB (IκB) blocks the translocation of p65/p50 and c-Rel/p50 dimers to the cell nucleus in the canonical pathway [8,9].The ubiquitination of IκB and subsequent degradation allows these proteins to be translocated to the cell nucleus, resulting in target gene activation.In the non-canonical pathway, NF-B-inducing kinase (NIK) induces the ubiquitination of p100 and its subsequent processing by proteasomes in p52.RelB/p52 is then translocated to the nucleus of the cell, where it activates target genes [8,9].The NF-κB pathway is closely linked to cancer biology and is elevated in most hematological and solid tumors [10,11].The NF-κB pathway can be activated by the loss of tumor suppressor genes, such as von Hippel-Lindau tumor suppressor (VHL), tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), and by the expression of some oncogenes, such as the BCR activator of RhoGEF and GTPase (BCR)/ABL proto-oncogene 1, rat sarcoma virus (RAS) family, and non-receptor tyrosine kinase (ABL).Moreover, apoptosis is increasingly induced when NF-κB is inhibited in cancer cells, corroborating the pro-survival and anti-apoptotic role of NF-κB in cancer cells [11][12][13][14].The activation of NF-κB subunits is triggered by long-term chronic inflammatory milieu or oncogenic alterations [15].Vascular disorganization promotes tissue injury due to hypoxia in the tumor microenvironment, and elevated NF-κB level activates inflammatory pathways [16].The tumor microenvironment of colorectal cancer (CRC) is aided by increased NF-κB activation [16].The NF-κB pathway is involved in several events in colorectal cancer stem cells (CRC-SCs), including preventing apoptosis, cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, invasiveness, and metastasis [15].
The suppression of MAPK and NF-κB signaling mechanisms could act in the robust inhibition of pancreatic tumor development; however, they were not found to exhibit apoptotic activities [17].The inhibition of matrix metalloproteinase-9 (MMP-9) expression by the Sabdariffa leaf extract may interfere with cancer invasiveness via the inhibition of the AKT/NF-κB/MMP-9 cascade pathway [18].The aforementioned studies provide evidence and state that the inhibition of NF-κB signaling pathway is associated with the inhibition of carcinogenesis.It has been found in CRC cell lines that the irregular activation of STAT3 and NF-κB signaling pathways could enable carcinogenesis [19].IKK/NF-κB in hepatic cells promotes hepatocellular carcinoma (HCC) growth by sustaining hepatic inflammatory responses [20].Inflammatory conditions trigger NF-κB in hepatocytes through the elevated expression of tumor necrosis factor-α (TNF-α) in neighboring inflammatory and endothelial cells.The suppression of NF-κB via anti-TNF-α therapy or by initiating the IκB super-repressor into the advanced stages of tumor progression leads to failure in HCC progression and apoptosis in transmuted liver cells, which established that the irregular inactivation of the NF-κB signaling pathway leads to the progression of HCC [21].Furthermore, in hepatitis B virus (HBV)-infected patients with malignant hepatoma and liver cirrhosis, the blood serum levels of TNF-α and interleukin-6 (IL-6) were found to be significantly higher than in those without these pathophysiological conditions [22,23].These investigations have proved that the persistently activated NF-κB signaling pathway induces enduring inflammation to facilitate carcinogenesis.Significantly, the NF-κB signaling pathway has intricate interactions with different signaling pathways.Different stimuli, including anti-inflammatory cytokines such as TNF-α, IL-1, and lipopolysaccharide, have been investigated for their stimulating behavior in the NF-κB pathway, which acts via binding to the IL-1R, TNFR, and the toll-like receptors (TLRs) [24,25].Upon triggering by the conforming ligands, receptor-interacting protein 1, TNFR-associated factor, and TNFR-associated death domain could be swiftly accumulated at the TNFR or TLR/IL-1R to construct complexes that employ and stimulate TGF-β-activated kinase 1 (TAK1).TAK1 eventually phosphorylates MKK4/7 (MAPK kinase 4/7) and IKK-β, which subsequently leads to the inactivation of JNK and NF-κB [26][27][28].Since the JNK signaling pathway enhances cellular proliferation and suppresses apoptosis, its communication with the NF-κB signaling pathway might intensify its tumor-promoting properties.Therefore, enduring inflammation may contribute to the inactivation of different signaling pathways via the interactions between them, resulting in amplified pro-tumorigenesis.

JAK-STAT pathway
JAK/STAT signaling is a critical signaling pathway in the development of cancer.It is directly implicated in cancer growth, progression, and metastasis, and is indirectly involved in immunosurveillance modulation [29].As the JAK protein is recruited and activated by cytokine receptors, cell signaling is activated.JAK then catalyzes tyrosine phosphorylation of the receptor, allowing STAT proteins to be recruited.STAT dimers are translocated to the cell nucleus after phosphorylation, where they bind to the DNA, causing the transcription of target genes [30,31].Several mechanisms can activate the JAK/STAT signaling pathway in cancer cells, the most well-known of which are mutations in STAT3 or glycoprotein 130 (GP130, also known as IL-6β), which boost independent activation of the STAT3 ligand in liver cancers and increase the release of cytokines, such as IL-6 [32].In CSCs, this signaling pathway induces enhanced tumorigenic capacity, metastasis, and chemoresistance in cancer via increased EMT [33].High STAT3 activity was found in tumor-infiltrating lymphocytes and CRC-SCs, but not in non-cancerous colon epithelia.In addition, a relationship between the JAK/STAT pathway and the tumor microenvironment was observed.Although STAT3 activity was lost in CRC-derived cells in culture, it was restored when these CRC cells were implanted in mice.Furthermore, inhibiting or blocking STAT3 activity in CRC-derived xenograft tumors inhibited tumor growth, supporting previous findings stating that STAT3 plays a direct role in CRC growth [34].
A current study employing a zebrafish tumorigenesis model to examine hepatocarcinogenesis conjectured a robust connection between JAK/STAT3 signaling and IL-6.Overexpression of IL-6 in zebrafish livers contributed to an enormous permeation of inflammatory cells and cytokines, which facilitated hepatocarcinogenesis and subsequent prognosis.Furthermore, the PI3K/AKT pathway was found to be activated.PI3K/AKT is known to be mostly active in infiltrated inflammatory cells, and the relationship between this pathway and JAK/STAT has yet to be completely elucidated, not only in HCC, but also in other tumors [35].
The overuse of indomethacin can lead to the stimulation of the JAK-STAT3 and NF-κB pathways, which can subsequently result in a poor prognosis of HCC [36].This poor prognosis can be predicted using activated STAT3.Apart from the prediction of cancer prognosis, the STAT3 pathway also functions as a therapeutic target.In cohorts with pancreatic ductal adenocarcinoma (PDAC), elevated levels of STAT3 have been linked to decreased survival and advanced tumor stage.Tumor growth is inhibited in the animal model as a result of STAT3 inactivation, which also enhances the therapeutic response in PDAC and can be exploited as a probable adjunct therapy for PDAC [37].In this regard, miR-34a was discovered to inhibit the STAT3 signaling pathway in cancer therapy.Similarly, p53-induced miR-34a was found to inhibit the EMT.In addition to miR-34a and STAT3, IL-6R promotes invasion, metastasis, and EMT in vivo and in vitro.STAT3 signaling pathway-induced chronic inflammation is inhibited to suppress tumor progression through the expression of miR-34a [38].Therefore, it could be inferred that the activation of STAT3 signaling promotes the occurrence and progression of cancer, whereas its inactivation may regress cancer.The role of Src homology-containing phosphatase1/2 (SHP1/2) in the feedback inhibition of STAT3 instigation, along with the negative correlation of IκB and STAT3 signaling pathways in human HCC tissues suggests the interactions of STAT3 and other signaling pathways [39,40].Additionally, multiple interactions between JAK-STAT3 and different signaling pathways are thought to stimulate malignant transformations.For example, ROS-induced oxidized SHP1/2, as a result of NF-κB signaling pathway interference, has no catalytic activity on the substrate of the JAK2 pathway [41].Hence, the JAK-STAT3 signaling pathway is activated.

MAPK pathway
MAPK, a type of serine/threonine kinase, can phosphorylate some cytoplasmic proteins and thereby regulate a panel of cellular programs such as cell differentiation, survival, proliferation, and motility.In mammals, there are more than a dozen MAPK enzymes.Conventional MAPKs are extensively studied, which include the extracellular signalregulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1-3 (JNK1-3), p38 (α, β, γ, and δ), and ERK5 families.Furthermore, there are supplementary, typical MAPK enzymes such as ERK7/8, ERK3/4, and Nemo-like kinase, which have distinct functions.MAPKs regulate a wide range of substrates, including candidates of a serine/threonine kinase protein family called MAPK-activated protein kinases (MAPKAPKs).MAPKAPKs are associated enzymes that respond to extracellular stimuli, thereby facilitating direct MAPK-dependent activation, loop phosphorylation, and subsequent kinase activation.There are five known MAPKAPK subfamilies: mitogen-and stress-activated kinase (MSK), p90 ribosomal S6 kinase (RSK), MAPK-activated protein kinase 2/3 (MK2/ 3), MK5 (also known as p38-regulated/activated protein kinase [PRAK]), and MAPK-interacting kinase (MNK).These enzymes have the potential to carry out various biological functions, such as regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival [42].
The classical MAPK cascade was initiated by MAPK kinase MINK (MAPKKK) activation.MAPKKKs belong to the family of serine/threonine kinases and can phosphorylate and subsequently activate MAPK kinases.MAPK cascades transmit signals via sequential activation of 3-5 layers of MAP4Ks, MAP3Ks, MAPKKs, MAPKs, and MAPKAPKs.The first three central layers are regarded as a core unit, while the remaining two layers appear in determining cascades, and can vary with stimuli and cells.Four MAPK cascades have been widely researched based on the components of the MAPK layer: ERK1/2, JNK, p38 MAPK, and ERK5.The ERK cascade involves several kinases in the MAP3K layer (mainly Rafs), including Ras/Raf/MAPK (MEK) 1/2 at the MAPKK layer, ERK1/2 at the MAPK layer, and several MAPKAPKs such as MAP kinaseinteracting serine/threonine-protein kinases, stress-activated protein kinase (SAPK), ribosomal s6 kinases, cytosolic phospholipase A2s, and MAPKs [43].
The MAPK signaling pathway is involved in managing diverse cellular behaviors such as differentiation, proliferation, survival, and apoptosis [44].Among the different MAPKs, JNK is the most studied.The three genes encoding the JNK proteins are JNK1, JNK2, and JNK3.Of these three, the first two are universally expressed, although the latter is limited primarily to the tissues of the brain and testes.JNK has a vital significance in cellular proliferation and apoptosis, and is typically stimulated by MKK4 and MKK7 [45].Similar to the rest of the MAPK cascades, the JNK signaling pathway controls cellular behaviors in different approaches, amidst which the carcinogenesis function of JNK and c-Jun, along with the regulation of cell growth, have been extensively investigated.Various studies have established that the involvement of JNK in cellular propagation or apoptosis is mediated by a few inflammatory cytokines, including IL-10 and TNF-α [46][47][48].Owing to the constant expression of inflammatory cytokines such as IL-10 and TNF-α, JNK is found to phosphorylate numerous substrates, including Bcl-xL, p53, JunD, Bax, Bid, JunB, ATF2, Bcl2, Bad, and c-Jun proteins, thus controlling cellular growth and apoptosis [49].Subsequently, phosphorylated JunD can upregulate the gene cIAP2 (a potentially effective apoptosis repressor) that comprises a single complex promoter with NF-κB binding sites and tandem apoptosis protein-1 (AP-1), which could contribute to the synergistic cooperation and transcription of NF-κB and JunD/Fos dimers.This creates a regulatory circuit for the positive feedback mechanisms [45].JNK-activated JunD and NF-κB induce the expression of cIAP, which promotes the K63-linked polyubiquitination of upstream signaling molecules and thus contributes to TAK1 stimulation.TAK1 eventually phosphorylates MKK4/7 and IKK-β to trigger the signaling pathways of JNK and NF-κB [50].Although early JNK stimulation facilitated by TNFR1 enhances transient cell survival and proliferation, this effect is reversed by sustained JNK activation.Prolonged JNK stimulation induces Bax/Bak-induced apoptosis, which promotes internalization through the external membrane of mitochondria, and eventually, the outflux of cytochrome C initiates apoptosis [51,52].Activation of apoptosis by JNK is also achieved via phosphorylation of tumor suppressors such as p53, E3 ubiquitin ligase, and Itch homolog or via the activation of transcription of Fas-L, TNF-α, and Bak (apoptosis-inducing genes) [53][54][55][56].Thus, the JNK signaling pathway plays an intricate role in carcinogenesis; when the JNK pathway is activated for a sustained period, it leads to tumor suppression and cellular apoptosis, and upon transient activation, JNK promotes cellular proliferation and survival.
Of the MAPKs, the few highly pronounced are p38 proteins.The class of p38 has four members: p38δ, p38γ, p38β, and p38α; these are likewise termed SAPK 4, 3, 2b, and 2a, respectively, and are found in various tissues [57].MAPKK (MKK3/6) selectively activates p38 MAPK and is facilitated by dual phosphorylation of the motif Thr-Gly-Tyr [58].Interactions between the JNK, p38, and MAPK signaling pathways are found in numerous stages of cancer.In this case, it was inferred from a study that the elevated expression of p38 MAPK was significantly associated with enhanced postoperative survival (median overall survival = 2 years and 3.9 months; P = 0.041).This study included 36 patients whose tissues were examined for matched metastatic and primary pancreatic cancer.It was found that p38 suppression by SB202190 significantly enhanced cellular proliferation.Additionally, p38 activity was inversely correlated with pJNK expression.Furthermore, the suppression of JNK via SP600125 had a significant downregulating role on tumor xenograft growth with enhanced mechanistic action of p38 compared to the tumor deprived of p38 expression.Generally, p38 MAPK promotes the malignant form of pancreatic cancer by triggering the JNK signaling pathway [59].Cytokines such as GM-CSF, IL-1, TNFα, IL-6, MCP1, and IL-8 are stimulated during inflammatory conditions, and tumor invasion, adhesion, angiogenesis, and malignancy are controlled by p38 MAPK.Therefore, the signaling pathway of p38 conjectures a vital role in carcinogenesis, followed by inflammation.

PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR signaling pathway is a master regulator of cancer that regulates the cell cycle, quiescence, metabolism, and proliferation [60][61][62].After activation of the growth factor receptor protein tyrosine kinase, the conversion of phosphatidylinositol (3,4,5)-triphosphate (PIP3) to phosphatidylinositol 4,5-bisphosphate (PIP2) into the membrane is initiated, providing coupling sites to signal proteins such as AKT.The mTORC2 complex phosphorylates AKT at Ser473 in the penultimate step of AKT activation.AKT increases the production of target proteins by activating the mTOR complex 1 (mTORC1).The PI3K/AKT/mTOR signaling pathway has been linked to the biology of CRC-SCs in certain studies [63].Chen et al. demonstrated that human CRC xenografts overexpressed various components of the PI3K/AKT/m-TOR signaling pathway, including phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2, a PI3K regulatory subunit), in CRC-SCs [64].Mangiapane et al. found that high expression of erb-b2 receptor tyrosine kinase 2 (ERBB2) in CRC-SCs is associated with the activation of the PI3K/AKT pathway, promoting acetylation in the regulatory elements of the ERBB2 gene, using a collection of primary cell cultures growing on spheroids obtained from 60 CRC specimens [65].In patients with stage II CRC, mTOR expression is also associated with poor prognosis [66].Furthermore, a transcriptome comparison of CRC-SC primary cultures and their normal stem cell counterparts revealed that CRC-SCs have an enrichment of genes involved in PI3K/AKT and Wnt signaling [67].
Phosphatase and tensin homolog (PTEN) is a tumor suppressor that generally acts as a negative regulator of the PI3K/AKT/mTOR pathway [68].PTEN has often been found to be mutated, deleted, or epigenetically silent in a wide range of cancers, thereby facilitating processes such as tumor progression, metastasis, apoptosis inhibition, malignant transformation, and resistance to radiotherapy [69,70].Continued expression of inflammatory cytokines such as IL-3, IL-6, and IL-7 can result in the abnormal activation of AKT, which in turn phosphorylates a panel of downstream proteins, including glycogen synthase kinase-3 beta (GSK-3β), insulin receptor substrate 1 (IRS-1), and mTOR.Moreover, upregulation of vital proteins such as vscular endothelial growth factor (VEGF) and cyclin D1, which generally promote carcinogenesis, may result from the activation of mTOR signaling [71].

Wnt signaling pathway
Wnt derives its name from the fusion between two proteins: the Drosophila segment polarity gene wingless and the vertebrate homolog, integrated or int-1 [72][73][74].The Wnt pathway is triggered by the binding of Wnt to Frizzled proteins or LRP5 and LRP6.There are two recognized Wnt signaling cascades: the non-β-catenin-dependent (non-canonical) and the β-catenin-dependent (canonical) cascades.Successive transportation into the nuclei and stabilization of cytoplasmic β-catenin is a crucial hallmark of β-catenin-dependent signaling.However, signaling associated with non-β-catenin is remarkably enabled by pathways that include planar cell polarity and small GTPase proteins.Increased secretion levels of IL-1β, IL-6, and TNF-α cytokines have been shown to activate the canonical Wnt/β-catenin signaling pathway [75].
The suppression of the Wnt/β-catenin signaling pathway by miR-26b can significantly decrease the secretion of IL-1β, IL-6, and TNF-α cytokines, thus contributing to the suppression of malignant cellular proliferation and elevating the rate of apoptosis [75].This demonstrates that Wnt/β-catenin-induced inflammation could decrease cellular apoptosis and promote malignancy.It has been conjectured that the instigation of the Wnt/β-catenin signaling pathway is correlated with different cancers.For instance, Wnt/β-catenin signaling activation is speculated to contribute to hepatocarcinogenesis based on the finding that approximately 30 % of cases of primary HCC exhibit β-catenin mutations.In addition, the Wnt/β-catenin pathway is specifically activated in an osteosarcoma cell line subset [76,77].The elevated expression of miR-1207 could instigate the Wnt/β-catenin signaling pathway by suppressing the negative factors consisting of secreted FRP1, TCF-4 (ICAT), AXIN2, and inhibitor of β-catenin, thus contributing to tumorigenesis.This asserts that the miR-1207-induced Wnt/β-catenin signaling pathway activation could contribute towards carcinogenesis via the suppression of accompanying negative regulators.The knockdown of retinoid X receptor α (RXRα) decreases cyclinD1 expression by the inhibition of the Wnt/β-catenin signaling pathway.RXRα can also enhance the expression of cellular nuclear antigen proliferation via the activation of the NF-κB signaling pathway and decreasing the levels of p21.Therefore, irregular stimulation of NF-κB pathways and Wnt/β-catenin induced by RXRα may contribute to the proliferation of cholangiocarcinoma [78,79].Therefore, these studies indicate that the activation of Wnt/β-catenin signaling could contribute towards carcinogenesis.However, this has also been revealed in the NF-κB and Wnt/β-catenin pathways that exhibit intricate interactions.A higher expression of β-catenin correlates negatively with hiNOS activity (human inducible nitric oxide synthase) and NF-κB.Elevated NF-κB instigation has been observed in the absence of β-catenin.Therefore, Wnt/β-catenin signaling controls hiNOS expression through NF-κB interaction, and thus plays a vital role in the pathophysiology of inflammation-linked carcinogenesis [80].

TGF-β/Smad pathway
TGF-β acts as a tumor inhibitor by interfering with the cellular growth cycle during the initial phase of carcinogenesis.During the progressive mechanisms of carcinogenesis with a decline in the tumor inhibition function, TGF-β promotes cell proliferation.It has been observed in standard pancreatic cells that elevated levels of TGF-β could check cellular propagation via the phase hindrance of G1/S [81].Additionally, TGF-β can stimulate JNK under chronic inflammatory conditions, leading to carcinogenesis.Hep3B hepatocarcinoma cell line-derived mitochondrial-depleted ρ0 cells exhibited more belligerent features of migration and invasiveness compared to the parental cell line.In non-cancerous cells, TGF-β functions as a tumor inhibitor; however, it is also found to promote tumorigenesis under enduring inflammatory conditions [82].This is demonstrated by the regulation of His by the pathway of Smad/TGF-β via the activation of cellular Jun/AP-1, which is the negatively correlated gene in the JNK signaling pathway.

Targeting inflammatory signaling pathways in cancer
Increased activation of the systemic inflammatory response has been observed in advanced aggressive tumors, such as lung and pancreatic cancers [83].Cancer therapy, including radiation and chemotherapy, has been found to initiate a strong tumor-associated inflammatory response.Research in the past few decades has focused on developing targeted drugs with greater specificity for cancer cells, higher potency, and lower toxicity, owing to the inability of chemotherapy to distinguish between cancer and normal cells [84].Various methods, such as small-molecule inhibitors, plant-derived biomolecules, recombinant cytokines, local irradiation, neutralizing antibodies, dendritic cell (DC) vaccines, oncolytic viruses, TLR agonists, and specialized pro resolving Fig. 2. Targeting inflammatory signaling pathways by phytochemicals and small molecules.lipid mediators (SPM) have been explored to modulate inflammation in cancer therapy (Fig. 2).

Small molecules
Small molecule inhibitors are a class of cancer therapeutic agents consisting of multitargeted and highly selective kinase inhibitors, DNA damage repair enzymes, epigenetic regulatory proteins, and proteasomes, all of which are used against advanced, treatment-resistant cancers and recurrent metastatic cancers.Among the many receptor tyrosine kinase inhibitors, C-MET (a receptor tyrosine kinase) and FMSlike tyrosine kinase 3 (FLT3) inhibitors obstruct tumor growth by targeting inflammatory signaling pathways.Tumor resistance to cytotoxic and molecular-targeted therapy has been correlated with C-MET overexpression, which has also been related to poor prognosis.The C-MET receptor binds to its sole ligand, hepatocyte growth factor (HGF), thereby activating multiple downstream effector pathways such as PI3K/AKT, RAS/MAPK, focal adhesion kinase (FAK), STAT3/5, RAC/ RHO, phospholipase Cg (PLC-g), SHP2, c-SRC, and CRKL, which are responsible for the regulation of survival, cell growth, motility, and invasion [85].Crizotinib, capmatinib, cabozantinib, foretinib, glesatinib, and BMS-777607 are C-MET inhibitors, of which a few have been approved as cancer therapies, while some are undergoing clinical trials in various combinations [86].Cell differentiation, survival, apoptosis, and proliferation are closely related to inflammation signaling, such as RAS/MAPK/RAF, JAK/STAT, and PI3K/mTOR/AKT, which have been found to be activated by the autophosphorylation of a proto-oncogene-encoded transmembrane protein, FLT3 [87].FLT3 inhibitors have been approved for relapsed acute myeloid leukemia (AML) patients with FLT3-ITD mutations, and have been found to have superior clinical efficacy compared to conventional chemotherapy [88].The JAK/STAT pathway is a useful target for cancer treatment as it plays an important role in cytokine signal transduction, and is frequently activated in cell proliferation, survival, invasion, and malignancy [89].So far, four JAK inhibitors have been approved for use in clinical studies, of which fedratinib has shown efficacy in the treatment of non-small cell lung cancer (NSCLC).Multiple cancers, including AML, Hodgkin lymphoma, prostate cancer, neuroblastoma, and myeloproliferative disorders, have been effectively treated with another JAK inhibitor, lestaurtinib [90].Small molecule BAF inhibitors have been approved by the FDA for the treatment of advanced renal cell carcinoma (RCC), thyroid carcinoma type 1 and type 2, and unresectable HCC [91].Type1 small-molecule BRAF inhibitors, vemurafenib, dabrafenib, and encorafenib stabilize kinases by occupying the ATP-binding site, whereas sorafenib (type 2 inhibitors) binds to hydrophobic sites that are adjacent to the binding pocket of ATP [92,93].Studies on encorafenib (LGX818) have shown that it downregulates cyclinD1 in a glycogen synthase kinase 3β-independent manner and arrests the cell cycle in the G1 phase, resulting in autophagy after inhibiting the mTOR/70S6K pathway [93].
Certain mTOR and PI3K inhibitors have been approved for the treatment of cancer, as the PI3K signaling pathway activated in many tumors has been closely related to drug resistance.Idelalisib, a selective PI3Kδ inhibitor, has been found to be effective in treating relapsed chronic lymphocytic leukemia (CLL) patients [94], while the pan-PI3K inhibitor copanlisib has been found to be successful in relapsed follicular lymphoma [95].The FDA has approved duvelisib, an oral dual PI3Kγ and PI3Kδ inhibitor, for patients with relapsed or refractory CLL, small lymphocytic lymphoma (SLL), and follicular lymphoma [96].XL147 and ZSTK474, pan-class I PI3K inhibitors, serabelisib, PI3Kα inhibitor, IPI-549, a PI3Kγ inhibitor, and several dual PI3K/mTOR inhibitors, such as GDC-0084 (RG7666), bimiralisib, dactolisib (BEZ235), and gedatolisib (PKI-587/PF-05212384) are undergoing clinical trials for determining their therapeutic efficacy [97].Tumors with loss of PTEN function or PIK3CA mutations are acted upon by AKT inhibitors that are relatively slow, as compared with PI3K and mTOR inhibitors [98].Inhibitors of pan-AKT-like capivasertib, uprosertib, ipatasertib, and afuresertib act by preventing the activation of AKT and enhancing the antitumor activity of chemotherapeutic drugs, and are currently being evaluated in clinical trials [99].Two categories of mTOR inhibitors have been developed: rapamycin analogs (rapalogs), namely sirolimus (rapamycin), everolimus, and temsirolimus, have been approved for the treatment of many cancers, and work by inhibiting mTORC1 activity and ATP-competitive inhibitors that simultaneously suppress both mTORC1 and mTORC2.Vistusertib (AZD2014), P529, GDC-0349, CC-223, sapanisertib (TAK-228), and DS-3078a are clinically evaluated ATP-competitive inhibitors [100].Table1 lists small molecule inhibitors employed in various cancer types and their target signaling pathways.Although PI3K/AKT/mTOR inhibitors have shown moderate clinical efficacy in cancer treatment, treatment with these inhibitors may result in resistance.The reason behind this is that they undergo negative feedback regulation, owing to the crosstalk between the PI3K/AKT/mTOR cascade and the Wnt and MAPK signaling pathways.Proteosome inhibitors act on multiple signaling pathways to induce apoptosis.Neoplastic pathways involved in cell proliferation, invasion, metastasis, and angiogenesis are downregulated by proteasome inhibitors that deactivate NF-κB and activate JNK signaling pathways, resulting in caspase 3-and 7-mediated programmed cell death.Apoptosis is also indirectly induced by proteasome inhibition owing to the prevention of BAX, BIK, BID, BIM, and NOXA degradation, which are the pro-apoptotic family proteins.An increase in endoplasmic reticulum (ER) stress occurs when ubiquitinated proteins are not degraded owing to proteasome inhibition, which activates the unfolded protein response (UPR), leading to cell cycle arrest and subsequent apoptosis [97].Bortezomib, carfilzomib, and ixazomib are a few of the proteasome inhibitors (PIs) recently developed and approved by the FDA for use against multiple myelomas (MM).In addition, several small-molecule drugs that bind to the ATP-binding domain of TβR kinases, inhibiting their activity, are being studied.Galunisertib is a TβR kinase inhibitor that has shown therapeutic potential in some patients with cancer [101].LY3200882 is another highly selective next-generation potent ATP-competitive TβR inhibitor that has shown antitumor efficacy in patients with advanced metastatic cancer in phase 1 clinical trials [102].Despite possessing significant pharmacokinetic characteristics, cost, patient compliance, as well as ease of drug storage and transportation, these targeted small-molecule anti-cancer drugs have limitations, such as drug resistance and low response rate.

Employment of phytochemicals to tackle inflammation-mediated cancer pathways
Phytochemicals are plant-derived phenolic substances that have been reported to be important chemopreventive molecules that enhance the expression of antioxidants and the Nrf2-ARE signaling pathway [103].Phytochemicals modulate the autophagy/apoptosis balance, thereby regulating cell survival [104], and exert a wide range of actions on various molecular targets in signal transduction pathways [105].The carcinogenic process is slowed down by phytochemicals that target free radicals by complementary overlapping mechanisms [106].Phytochemicals induce tumor cell necroptosis, in addition to apoptosis [107], inhibit cancer malignancy and progression, and impede tumor invasiveness and angiogenesis [108].
Flavonoids (plant metabolites) show antioxidant properties and are capable of modulating signaling pathways such as MAPK/p38, PI3K/ AKT, apoptosis cascades, and Wnt, which ultimately associate them with anticancer properties [109].These metabolites promote cellular differentiation, apoptosis, and cell cycle arrest, thereby inhibiting cell proliferation, angiogenesis, and metastasis.Flavonoids can be subdivided into a number of classes based on their anticancer properties, such as isoflavones, flavones, flavonols, flavanones, anthocyanins, and chalcones [110].The flavonoid apigenin is a potent AKT inhibitor that has oncogenic effects on various cancers.In a study with NSCLC cells, apigenin was found to target the interplay of AKT and Snail/Slug signaling, thereby downregulating CD26/dipeptidyl peptidase IV (DPPIV), which suppressed EMT and the invasive ability of NSCLC cells [111].In several recent studies, quercetin, another flavonoid, has been reported to be a potent anticancer agent, capable of modulating survival, proliferation, and differentiation of tumor cells by inhibiting EGF-induced EMT via the EGFR/PI3K/AKT pathway [112].Another polyphenol that regulates tumor cell growth and has gained a great deal of attention in cancer therapeutics is curcumin, which modulates numerous cell signaling pathways, including AKT, sonic hedgehog, Wnt/β-catenin, NF-κB, and STATs, epidermal growth factor receptors (EGFR and erbB2), as well as metastatic and angiogenic pathways [113,114].Table 1 lists small molecules and phytochemicals used to target inflammatory signaling pathways in cancer therapy.In oral, esophageal, and colorectal cancers, curcumin downregulates Notch-1 [115].Although curcumin is free from extreme toxicities and is extremely efficacious, its therapeutic potential is limited owing to its poor bioavailability.Another active triterpene molecule, nimbolide (Table 1), has been reported to exhibit anticancer properties, inhibiting pancreatic cancer growth and metastasis.Treatment of pancreatic cancer cells with nimbolide led to a reduction in AKT activation, which further reduced mTOR activity and its downstream target, P70-S6 kinase, which ultimately resulted in the inhibition of cancer cell proliferation.Nimbolide also targets Ras/Raf/MEK/ERK signaling, which lowers phosphorylated ERK levels and decreases invasion, migration, and anchorage-independent growth potential of cancer cells, thereby reducing the aggressiveness of pancreatic cancer cells.It blocks EMT by downregulating pro-EMT markers, such as Notch-2, Snail, N-cadherin, Zeb, vimentin, and Slug, while increasing the expression of epithelial marker E-cadherin-3 thereby eliciting anti-metastatic effects [116].In another study, withaferin A, a bioactive phytosterol, was found to inhibit growth, migration, and invasion of HCC cells by increasing the phosphorylation of ERK and p38 in HCC.Withaferin A also resulted in significant inhibition of AKT activity, which further affected NF-ĸB activity in colorectal cancer cells and downregulated EMT markers, leading to the inhibition of cell proliferation, migration, and invasion [117].As phytochemicals pose little toxicity to the surrounding normal cells despite having significant effects on cancerous cells, the anticancer and chemo-preventive properties of phytochemicals are of growing interest to researchers.However, well-controlled, more extensive, large-scale clinical trials are needed to identify any adverse side effects and to validate their efficacy before implementing them in cancer therapy [118].

Nanomedicineas an avenue in cancer chemotherapy and theranostics
Nanomedicine has opened doors for the improvement of cancer treatment by adding to existing drug delivery platforms.Advances in nanomedicine have provided new opportunities for the early detection and diagnosis of cancer as well as improved effective treatment.By modulating the biodistribution of nanomedicines and their target site accumulation, we can improve the balance between the toxicity and efficacy of systemically administered chemotherapeutic drugs.Depending on their unique physical, chemical, mechanical, and optical properties, nanomaterials deliver therapeutic molecules, such as drugs, proteins, or nucleic acids, as nanocarriers.Research in the field of nanomedicine is aimed at developing nanoscale drug delivery strategies, involving functionalization of these constructs with moieties that favor site-specific tailored release of the drugs.Several NP technologies, such as liposomes, nanogels, polymer micelles, and dendrimers, can overcome numerous biological barriers involved in drug delivery [145].

Discrete nanoparticles in cancer treatment
NPs used for drug delivery have varying biophysicochemical properties, such as different sizes (range, 1 nm-100 nm), shape, surface, and materials used (soft, organic, polymeric, hard, or inorganic materials) [146].Nano-drug delivery systems (NDDS) can be divided into three vector generations: nano-capsules and nanospheres comprising the first generation; second-generation nano-vectors, including those coated with hydrophilic polymers, such as polyethyleneglycol (PEG); third-generation vectors consisting of those with a polymer envelope combined with a functionalization agent around a biodegradable core.These systems have multiple advantages, such as protection of the drug from degradation in the body, enhanced drug absorption, controlled drug distribution to specific tissues, and limited toxicity to normal cells.
Targeted polymeric nanoparticles (PNPs) used as drug carriers in cancer therapeutics have many advantages, such as non-toxicity, biodegradability, biocompatibility, prolonged circulation, and a wide payload spectrum.PNPs are colloidal particles of submicron size with an anticancer agent encapsulated inside the PNPs or adsorbed onto the surface.Drug-loaded PNPs are used for the sustained release of anticancer therapeutics to specific sites in targeted drug delivery systems (TDDS).For this purpose, the polymer composition, crystallinity, molecular weight, solubility, hydrophobicity, polydispersity, and other characteristics were designed in accordance with the charge and molecular weight of the drug to be carried.Poly (lactide-co-glycolide) (PLGA) (synthetic), polyhydroxyalkanoates (PHAs) (natural), and cyclodextrins (CDs) (synthetic) are important PNPs employed for TDDS.Other organic NPs, including nanomicelles, are made of amphiphilic blocks, as their core has hydrophobic blocks that can hold hydrophobic drugs and an outer hydrophilic corona [147].In several studies, PEG polymeric micelles have been reported to deliver cytotoxic drugs to cancer cells [148].Likewise, liposomes are bilayer NPs that are ideal for encapsulation of nucleic acid-based components, such as siRNA and plasmid DNA, in their hydrophilic core and resemble phospholipids and cholesterol.These spherical structures with a single lipid bilayer are suitable for water-soluble drug encapsulation, whereas lipid-soluble drugs are entrapped within liposomes with more than a single bilayer.
For the treatment of metastatic breast cancer, liposomal formulations carrying anthracyclines, doxorubicin, and daunorubicin have been clinically approved [149].Polymeric nanogels, made by crosslinking polymer chains, produce an inner porous space for carrying large volumes of payload, and hence can simultaneously deliver multiple drugs.Nanogels are prepared using different cross-linking methods, such as ionic cross-linking, functional group cross-linking, self-assembly, crystallization, cross-linking polymerization, and radiation cross-linking.Temperature-sensitive and pHsensitive nanogels have been prepared as their network structures contain a large portion of water within them, which gives them responsiveness to temperature and the presence of ionizable repeating groups in the polymer chains susceptible to pH-dependent release [150].PEGylated nanogels deliver their drug load into tumors following intravenous injection after an improved circulation time.Dendrimers such as polyamidoamine (PAMAM), polyglycerol (PG), poly (propylene imine) polyamide, and triazine are a few other organic PNPs that can perform multiple functions at their terminal groups.The branches of these uniform tree-like structures formed by assembling monomeric subunits are complexed with functions such as targeting ligands, imaging agents, and other drugs, while the internal star structure carries the drug payload [151].
Inorganic NPs are useful in cancer detection and diagnostic applications because of their photochemical, photothermal, and magnetic properties, and feasibility owing to their complex, durable cores and rigid outer surface with various kinds of drug agents.Several magnetic NPs, such as superparamagnetic iron oxide particles, have been used in image contrast and magnetic resonance imaging (MRI) for tumor detection.The diagnostic capability of these NPs can be enhanced by the complexity of surface modifications of these molecules with targeting functionalities, such as therapeutic superparamagnetic iron oxide nanoparticles (SPIONs),which are made of an iron oxide NP core that carries both contrast agents for MRI as well as therapeutic drugs, and the coating on the surface is favorable for interactions between biological systems and SPION [152].Furthermore, gold NPs are used in tumor imaging owing to their optical and electrical properties, and have been described as "promising nanocarriers for therapeutics" because of their easy synthesis and functionalization, relative biocompatibility, and low toxicity [153].These NPs can be easily modified as they present negative reactive groups on the surface and a core of gold atoms.Ultra-small gold NPs are uniformly distributed within the tumor tissues owing to their ability to diffuse through tissues; however, their use is limited by poor uptake.Semiconductor NPs called quantum dots (QD), owing to their quantum and size effects, have unique optical properties, which make them useful as imaging probes [154].The most commonly used QD system is composed of an inner semiconductor core of CdSe coated with a ZnS outer shell.QDs are also used as biosensors for cancer diagnosis owing to their unique properties, such as prolonged, stable, and intense fluorescence, resistance to photobleaching, and highly sensitive detection [155].Moreover, some organic polymers have been fabricated along with gold NPs and QDs to form hybrid systems in order to achieve drug packaging and diagnostic capabilities for effective drug delivery along with treatment response and real-time monitoring of tumor activity [156].A class of fluorescent NPs, called lanthanide-doped NPs, allows for the conversion of near-infrared (NIR) and low-energy light to high-energy visible light or ultraviolet emission, which has been exploited in cancer diagnosis as well as imaging-guided NIR laser irradiation of tumors [157,158].
Novel research in DNA nanotechnology has brought DNA nanocarriers and DNA origami for targeted drug delivery.Other DNA nanostructures, such as DNA hydrogels, have also been used to deliver drug molecules loaded inside their porous cavities.A DNA origami technique is used to regulate the entry of therapeutic drugs into cancer cells by constructing nanopores that enable their utilization as biosensors or drug carriers through modifications in DNA nanostructures with functional groups.DNA origami nanostructures possess a number of advantages, such as enhanced chemotherapy efficacy and reduced adverse side effects, and are capable of circumventing drug resistance [159].Another promising approach to target cancer cell growth and metastasis is to deliver small interfering RNA (siRNA) and short hairpin RNA (shRNA) to target cells that knockdown target gene expression by RNA interference-mediated post-transcriptional gene silencing.siRNA is not administered directly into living organisms because of its high instability and destruction by the immune system; therefore, a nanoparticulate RNA delivery system needs to be developed for gene therapy in cancer treatments [160].

Nanomedicines targeting inflammatory signaling pathways
After advances in nanotechnology, polymer-drug conjugates such as NPs in combination with other small molecule inhibitors, phytochemicals, and siRNA, are one of the most dominant classes of therapeutic products in cancer treatment owing to their high pharmacological efficacy.In some cancer therapeutic approaches, NPs are used to encapsulate active compounds for easier drug delivery.NPs can be used to arrest the cell cycle in cancer cells by modulating mTOR activation [161].A class of nanomaterials developed for clinical applications, PAMAM, deregulates the AKT-TSC2-mTOR signaling pathway, triggering autophagic cell death [162].Similarly, SiO 2 NP inhibits the PI3K-AKT-mTOR signaling pathway by deregulating the NO-NOS system, thereby triggering an inflammatory response resulting in autophagy in cancer cells [163].Moreover, amino-functionalized polystyrene NP treatment in leukemia cell lines has been found to block proliferation and vascularization by initiating G2 cell cycle arrest through the inhibition of mTOR signaling pathways [164].Furthermore, COOH-functionalized carbon nanotubes also modulate the AKT-TSC2-mTOR pathway exerting an extreme autophagic effect on the cells [161].Fig. 2 and Table 2 summarize some presently used engineered NPs in cancer therapeutics that modulate inflammatory signaling pathways.
PHAs are produced by various microorganisms during growthlimiting conditions.These biodegradable, biocompatible, and natural polyesters conjugated with NPs and bioactive substances such as hAGP, hEGF, folic acid, RGD (peptide), and PI3Ks inhibitors have been used for TDDS by targeting the active tumor [137].TGX221, a controlled release PHA-NPs carrying a PI3K inhibitor, has been found to inhibit the growth of prostate cancer, breast cancer, and colorectal carcinoma [138].A few PLGA-based NPs have been used for active tumor targeting in both in vitro and in vivo trials.Receptor-ligand interactions of PLGA-based NPs in cancer therapy have been used to increase the apoptosis rate in cancerous cells by downregulating STAT3.In lung cancer cells, PTX and STAT3 siRNA have been co-delivered using PLGA NPs and have been found to overcome cellular resistance [139].In a study, drug-resistant lung cancer cell lines most efficiently took up the PLGA-PEI-TAX-S3SI NPs in comparison with free PTX, and induced a higher level of cellular apoptosis in the treated cells [137].In another study, the application of a drug delivery system based on hybrid NPs of self-assembled aptamer-lipid PLGA was studied for two anticancer drugs, namely DOX and PTX, considering the possible mechanism and solubility patterns [140].

Nanoparticles conjugated phytochemicals as nanomedicine
Although increasing research supports the anticarcinogenic roles of phytochemicals that regulate cellular events such as cell proliferation, apoptosis, migration, and invasion by modulating various signaling pathways, their clinical use faces challenges such as low water solubility, poor absorption, instability, and rapid metabolism.To maximize the use of phytochemicals in anticancer treatment, researchers have developed novel formulations.For this purpose, nanocarriers are being used to increase the half-life of phytochemicals in the circulation, along with their solubility and stability, thereby enabling targeted delivery [165].Nanoparticulate-based drug delivery systems hold promise in cancer therapy, as these nano-sized natural compounds exhibit drastically reduced toxicities apart from altered bioactivities.
As seen earlier, quercetin and its metabolites play crucial roles in the elimination of cancerous cells by targeting multiple pathways; however, its therapeutic effects are restricted owing to its poor solubility in aqueous solutions.Studies with breast cancer cell lines have shown that Au NPs loaded with quercetin (Qc-AuNPs) successfully inhibit the EMT by inhibiting the transcriptional repressors Snail, Slug, and Twist, as well as angiogenesis and invasiveness via EGFR/VEGFR-2-mediated pathway, and induce apoptosis via inhibiting the EGFR/PI3K/protein kinase B (AKT)-mediated pathway.Qc-AuNPs also upregulates the expression of the epithelial marker, E-cadherin, and downregulates mesenchymal markers of N-cadherin and vimentin protein expression, which leads to decreased migration and invasiveness of cancer cells [166].AuNPs-Qu-5 has been identified as a potential drug delivery system in breast cancer therapy and has been found to be more potent than free quercetin in causing cancer cell death [167].Curcumin and epigallocatechin-3-gallate phytochemical-capped silver nanoparticles (AgNPs) interact with human serum albumin, the most abundant protein in biological fluids, and have been implicated in the development of new opportunities in nano-diagnostics and nanomedicine [168].Other phytochemicals that have been conjugated with nanocarriers to amplify their therapeutic effects include apigenin (4,5, 7,-trihydroxyflavone), resveratrol (3,4,5-trihydroxy-trans-stilbene), and 6-Gingerol (1-(4-hydroxy-3-methoxyphenyl)-5-hydroxy-3-decanone) [165].

Inhibits STAT3 Increases level of apoptosis and inhibition of cell proliferation
Ovarian cancer cell lines (A2780CP and A2780ss) [190] Liposome-siRNA complex
N.K. Jha et al. 4.4.siRNA and shRNA delivery to cancer cells targeting inflammatory pathways RNA aptamer molecules have been used to alter tumorinflammation-related cells by introducing siRNA molecules into the tumor as a means of novel cancer therapy.These molecules induce immune stimulation and exert reduced toxic effects; however, for therapeutic use, they need to be encapsulated within a drug delivery system as they cannot enter the cells because of their high hydrophilicity, negative charge, and relatively high molecular weight [169].Studies focused on breast cancer-induced bone metastasis showed that the use of STAT3-targeting siRNA loaded onto E-selectin thioaptamer-conjugated multistage vesicles (ESTA-MSV) significantly increased survival rates in the treated mice [170].Lung cancers are targeted using siRNA delivered by chitosan-based NPs coated with cyanoacrylate, resulting in the inhibition of tumor growth [171].siRNA delivered by DOTAP (lipoplex)-based NPs successfully inhibited TNF-α expression.Since HER-2 leads to increased cell growth, survival, and angiogenesis through the activation of MAPK, PKC, and PI3K signaling pathways, knockdown of the gene responsible for HER-2 overexpression has been successfully carried out using immune-liposome nano-vectors with an anti-transferrin antibody [172].In a study on breast and lung cancers, RNA interference was employed to suppress the RAS/MEK/ERK and PI3K/AKT/mTOR pathways to inhibit cancer metastasis [173].Moreover, LCP-based NPs inhibit c-Myc transcriptional factor, which is overexpressed in NSCLC.siRNA has been co-administered with chemical drugs to enhance the quality of tumor cell treatment; for instance, siRNA, along with the chemical drug gemcitabine monophosphate, was delivered using LCP-based NP, which was found to cause a significant amount of tumor cell apoptosis, as well as a reduction in tumor cell proliferation, without much toxicity to neighboring cells [174].In a study on lung cancer cells, folate-chitosan graft PEI conjugated with shRNA was used to suppress tumor angiogenesis by blocking the AKT signaling pathway [175].STAT3 expression was downregulated in pancreatic cancer cells using STAT3 shRNA expression vectors, which led to a marked decrease in the metastasis and malignancy of pancreatic cancer cells [176].Anti-STAT3-loaded PLGA NPs have been found to target dendritic cells in melanomas and have proven to be promising agents in cancer immunotherapy [177].STAT3-siRNA-loaded NPs have demonstrated high efficacy in decreasing cancer cell malignancy owing to their high cellular uptake by tumor cells (Fig. 3).

Recent advances in cancer nanomedicine via inflammationsignaling pathways
With the increasing establishment of links between carcinogenesis, tumor-linked inflammation, and metastasis, anti-inflammatory drugs used earlier in the treatment of inflammation are now being exploited as cancer therapies.Anti-inflammatory drugs can be categorized into glucocorticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) [195].NSAIDs inhibit the growth of a number of tumors by blocking COX activity and modulating the NF-κB pathway, among other key inflammatory pathways [196].Curcumin loaded in lipid-polymer NPs called NANOCurc curbs the vascular accumulation of circulating tumor cells [197].In a different study, researchers loaded docetaxel (DTXL) and curcumin together in curcumin-conjugated cholesteryl-hyaluronic acid nanogels (CHA-CUR) as well as spherical polymeric nano constructs (SPNs), which resulted in a 13-fold tumor suppression [198].A research group co-loaded aspirin and the antioxidant ferulic acid into chitosan-coated solid lipid NPs (c-SLNs) to improve the pharmacokinetics of aspirin, significantly increasing pancreatic cancer suppression [199].Improved efficacy of ketoprofen-loaded nano capsules (Keto-NC) has been tested clinically in glioma cancer models [200].In addition, a significant reduction in lung cancer volume compared to control groups Fig. 3. Nanoparticles targeting inflammatory signaling cascades in cancers.

N.K. Jha et al.
with increased ibuprofen efficacy was observed with the use of phospho-ibuprofen amid (PIA)-loaded nanocarriers [201].
Glucocorticoids are already successful chemotherapeutics used in treating inflammatory carcinomas such as multiple myeloma, Hodgkin's and non-Hodgkin's lymphomas, lymphocytic leukemia, and breast cancer [202].However, further improvements in efficacy of these steroids have been observed when they were loaded into nanocarriers; dexamethasone (DEX)-loaded liposomes and prednisolone-associated gellan gum nanohydrogels (Ge-Pred NH) loaded with paclitaxel (PCT) significantly reduced prostate cancer bone metastases [203,204].
Another approach to monitor tumor progression and metastasis is to formulate nanocarriers capable of reprogramming tumor associated macrophages [205,206].To enhance the ability of MnO 2 NPs to modulate chemoresistance and reduce tumor hypoxia, mannan-conjugated, hyaluronic acid (HA)-coated MnO 2 NPs (Man--HA-MnO 2 ) have been fabricated, which downregulate HIF-1α and VEGF inhibiting breast tumor growth when used in combination with doxorubicin [207].Recent developments in theranostic NPs have been carried out where diagnostic moieties can be conjugated to therapeutic NPs or vice versa.These include the use of micellar constitution of hydroxy-benzyl alcohol-combined copolyoxalate (HPOX) coupled to a fluorescent dye that detects H 2 O 2 generated in inflamed tissues [208].In cases of deep-seated tumors, gold NPs are easily detected using different imaging and diagnostic techniques.Gold nanorods coupled with doxorubicin with a mesoporous silica coating were fabricated to successfully increase the payload volume [209].The imaging properties of magnetite, along with the ability of liposomes to deliver versatile payloads, have been exploited in designing magneto liposomes for targeting cancer-associated inflammation [210].Currently, biomimetic nanovesicles, called leukosomes, are being developed for the selective delivery of therapeutics to tumor-associated inflamed vasculature.These medicines mimic the natural characteristics of the body and aim to increase targeting and prolong NP circulation within the body by replicating real cell-like interactions.

Nanomedicine-related challenges for targeting inflammatory signaling pathways in cancer
The use of NPs as drug delivery systems faces multiple challenges, such as biodistribution, pharmacokinetics, and possible toxicity.The success in the translation of the use of PNPs in targeted drug delivery from preclinical approaches to clinical trials for cancer therapy remains limited.Some of the challenges faced during TDDS fabrication include limited interaction between ligand and receptor, over-expression of markers (present on the targeted surface) located on the surface of normal as well as cancerous cells, difficulty in delivering the therapeutic agent in precisely small amounts to the tumor site, and NP accumulation in non-targeted areas, resulting in nano-toxicity [211].
Unfavorable interactions of NPs with biological entities is another challenge in drug delivery, which leads to unwanted toxicity [212].As the physicochemical properties of nanoformulations vary from batch to batch, their large-scale production is also quite challenging.In conjunction with physicochemical properties, the pharmacological performance of nanomaterials may also be influenced by NP storage and stability [213].To avoid nanocarrier toxicity to healthy cells, nanomaterials for drug delivery need to be carefully synthesized and characterized.When NP structures are inside biological environments, they are covered by a biomolecule layer called a protein corona responsible for stimulating the subsequent interactions of cells with the triggered NPs [214].This protein corona is responsible for tissue penetration, cell internalization, and interaction with the microenvironment of the perivascular tissue [215].The protein corona absorption on the surface of NPs causes them to lose their targeting capabilities by reducing the adhesion between NPs and the cell membrane and mitigating the disruption of cell membranes performed by bare NPs [216].Additionally, these proteins undergo conformational changes that can alter the cell recognition of NP, thereby initiating alternative cell signal transduction [217].NPs have also been found to induce protein aggregation, which affects the targeting capabilities and toxicity of NPs [218].The adsorbed proteins negatively impact the specificity of NPs and support mTOR activation in cancer cells, thereby inducing cellular apoptosis [219].However, limited knowledge exists regarding the significant mechanisms that have the potential to drive the effects of NPs related to mTOR on tumor cells.

Market status of cancer nanomedicine and challenges in clinical translation of chemotherapeutic agents
Limitations of conventional cancer remedies have led to the emergence of cancer nanomedicine as a groundbreaking and promising alternative therapeutic modality, providing new avenues for early detection, improved treatment, better prognosis, and efficient cancer diagnosis.The global nanotherapeutics market is expected to reach 334 billion dollars by 2025, with cancer nanomedicine accounting for the major market share.The burgeoning interest in utilizing nanotechnology to manage and treat cancer is attributable mainly to its unique structural features as well as the therapeutic nature of some of the nanomaterials themselves.Nanotherapeutics that include some of these features (e.g., improved circulation and decreased toxicity) are already currently in use, and others have shown encouraging results in clinical development, with conclusive results expected soon.Some of the approved nanotherapeutics include NP platforms, such as liposomes, albumin NPs, and polymeric micelles.Other nanotherapeutic modalities currently under clinical investigation include hyperthermia, chemotherapy, radiation therapy, gene or RNA interference (RNAi) therapy, and immunotherapy.Despite the capability of cancer nanomedicines to deliver dose-specific chemotherapeutic agents (with limited toxicity), it is essential to consider the tumor complexity and dynamics for connecting the translational bench-to-bedside gap.The complexity and heterogeneity of tumors requires careful patient selection to identify those who would benefit the most from a given nanomedicine.Moreover, there is a need to understand the complexity of the tumor microenvironment and the nano-bio interactions within tumors to achieve a more detailed insight into the fundamental biological processes in cancer and their roles in moderating NP-protein interactions, blood circulation, and tumor penetration [220,221].Combinatorial therapies have shown greater efficacy in chemotherapy than monotherapy; hence, combination therapies to enhance the protective capabilities of nanomedicines are constantly being investigated.Since the approval of liposomal doxorubicin (Doxil) and daunorubicin (DaunoXome) for the treatment of HIV-related Kaposi's sarcoma, significant investment and research have gone into the development of cancer nanomedicines.The benefits of formulating cancer drugs in lipid-and polymer-based nanocarrier systems include improved drug solubility, circulation time, biodistribution, and reduced toxicity while maintaining or even augmenting their therapeutic efficacy, leading to the approval of several cancer nanomedicines, including antibody-drug conjugates (ADCs) and microbubbles [222,223].These nanomedicines include local, topical, and systemically administered organic and inorganic particles.
Clinically approved nanomedicines are often classified based on material composition, belonging to the lipid, polymer, protein, or metalbased nanomaterial category.An alternative classification of nanomedicines is based on their ability to improve therapeutic efficacy.The full potential of nanotechnology in medicine remains unexplored as nanomedicines that exploit a broad set of nanoscale benefits are yet to reach the clinic.Though therapeutic molecules (chemical, biological, or nanotechnological) have proven to be highly effective and cell-selective in targeting a subset of cancer cell populations in vitro, and even in suitable animal models, they have failed during clinical trials.The biodistribution of the agent may be a factor contributing towards these setbacks, with insufficient or improper concentrations of the compound being released at target sites while there is unwanted concentrations elsewhere, driving dose-limiting toxicities.
The biodistribution of therapeutic compounds is largely moderated by the drug's ability to penetrate biological barriers, especially in the evolving forms they present in the course of tumorigenesis.The longterm strategy of attaching targeting moieties to therapeutic NPs to increase their systemic localization specificity has not yielded encouraging results.This pitfall is linked to the fact that the addition of molecular targeting agents augments recognition specificity, but at the cost of much more significant difficulties in trespassing the biological barriers [223].Nevertheless, significant advantages of nanomaterials include their unique electromagnetic features and distinct transport properties.Owing to the multifunctional role of nanomaterials, many of these properties have been exploited in clinical settings.However, successful future of cancer nanomedicines will likely have to integrate nanomaterial properties that can be used to target and modify the tumor microenvironment.Nanomedicine can substantially improve the prognosis of aggressive tumors in clinical oncology, such as triple-negative breast cancer (TNBC) and pancreatic cancer.Pancreatic cancer requires a multi-pronged treatment approach, as the tumor microenvironment presents unique challenges owing to the dense stroma and poor vascularization.In regard to TNBC, NP-based therapeutic approaches have shown promise in overcoming drug resistance and achieving site-specific delivery through innovative techniques such as hemodynamic targeting.However, improved understanding of bio-nano interactions in the body is required, as this interface is a determining factor in the success of nanotherapeutics.Therefore, systematic investigations that assess the impact of NP characteristics on biomolecular interactions and pharmacokinetics are critical for designing novel treatments.Furthermore, it is important to consider that the commercialization process for cancer nanomedicines is challenging owing to a lack of industry experience in large-scale clinical-grade manufacturing.Current pharmaceutical production facilities specialize in the production of small molecules and antibodies [224].
Therefore, where do cancer nanomedicines stand after close to two decades of research?It has been difficult to fulfill the stringent requirements of cancer nanomedicines that arose regarding the clinical translation, after the approval of liposomal doxorubicin and daunorubicin.The fact that these expectations were created by overgeneralization of drug targeting and delivery techniques and the exaggeration of the predictive value of pre-clinical results means a more pragmatic view on the potential and limitations of cancer nanomedicines can also be created, which fortunately appears to be happening at present.Nevertheless, fundamental research should continue to discover new materials and identify new avenues for nanomaterial-mediated cancer therapy, possibly learning from nature's innate delivery systems, without overselling pre-clinical results.It is imperative to fundamentally understand the therapeutic window of cancer nano-modalities by further investigating their interactions in the body.It is essential to develop clinically relevant cancer nanomedicines that benefit patients in the long term, and translational research, therefore, should adopt a "disease-driven" approach rather than a "formulation-driven" one [223].

Nanophytomedicine as a novel therapeutic modality
Phytomedicine has been existing since ancient times.Today, approximately 50 % of essential drugs are derived from natural sources.The use of phytomedicine has increased over the last decade owing to better therapeutic activity and fewer side effects, as compared to allopathic medications.Phytomedicines have shown impressive in vitro activity but less in vivo efficacy owing to their poor water solubility, lipophilicity, and inappropriate molecular size, resulting in poor absorption and systemic availability.A better understanding of the biopharmaceutics and pharmacokinetics of phytomedicine can help address some of these concerns and help design rational dosage regimens.As discussed earlier, the use of nanotechnology-based tools for the treatment, identification, monitoring, and management of biological systems has tremendous potential.In phytomedicine research, incorporating the nano-based formulation has several advantages, including improved solubility and bioavailability, enhanced pharmacological activity, safeguarding from toxicity, increasing tissue macrophage distribution, improving stability, sustained delivery, and safeguarding from physical and chemical degradation [225].
The development of nanophytomedicines, reducing the size of phytomedicines, or attaching polymers with phytomedicines, along with modifying the surface properties of herbal drugs can increase the solubility, permeability and, eventually, the bioavailability of phytomedicine formulations.Novel formulations such as niosomes, liposomes, nanospheres, and phytosomes can be exploited [226].However, it must be kept in mind that nanophytomedicine requires a scientific approach (that is more biological) to deliver the components in a sustained manner to increase patient compliance and avoid repeated administration.This can be achieved by formulating novel drug delivery systems (DDSs) for herbal constituents.These DDSs can help reduce repeated administration to overcome non-compliance and help enhance therapeutic value by limiting toxicity and increasing bioavailability.Hence, integrating NPs as DDS in the traditional medicine system can help combat more chronic diseases such as asthma, diabetes, and cancer [227].

Conclusions
The instrumental role played by inflammation during all phases of tumor progression necessitates research to uncover its mode of operation and molecular and cellular mechanisms in early tumor initiation and metastasis.Research on the mechanistic activities of protumorigenic inflammatory pathways in tumors and cancer has revealed that the induction of inflammation in the tumor microenvironment can occur before or after the initiation of tumorigenesis or may become obvious in the post-tumorigenesis phases.Although several targeted strategies have been identified for inflammation-targeting cancer therapy that progress by either promoting cancer-inhibiting inflammation or inhibiting cancer-promoting inflammation, there is a need to develop ideal drug delivery platforms that limit the degradation/modification of drugs in the circulatory and monocyte phagocytic systems, thereby increasing their biodistribution and pharmacokinetics and reducing their off-target effects.A wide range of NPs, bioflavonoids, phytomolecules, and small molecules have been employed in various targeting strategies with immune-related antitumor effects, the most widely targeted being PI3K-AKT pathway inhibition, MAPK signaling inhibition, and STAT3 inhibition.Both NF-κB and STAT3 represent potential tumor-promoting mechanisms by interfering with p53 synthesis and upregulating the expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL.Many of these compounds target cancer-related signaling pathways and constrain migration, invasion, and adhesion, as well as triggering Bax proteins to induce apoptosis.These anti-inflammatory and anti-tumor therapies need to be combined into precision treatments; however, there is still a long way to go for their clinical application.Research needs to be carried out to project low-toxicity anti-inflammatory combinations to target inflammation-associated signaling pathways across the phenotypic ranges of cancer.Targeted studies are required to address the complications of bioavailability postured by several factors such as the use of nano-delivery systems, liposomes, implantable polymeric micelles, phospholipid-based delivery systems, and microspheres, which have been recently conjectured to address this issue.As we put efforts in solving the complications of existing cancer therapies, cautious contemplation is required to implement any multi-pronged approach that emphasizes the aim of these signaling pathways to decrease toxicity and increase the scope of immunomodulation to exhibit high significance for anticancer effects.

Fig. 1 .
Fig. 1.Systemic chronic inflammation and cancer progression.(1) Different cell types are present in tumor microenvironment (TME) and each representing a diverse impact on cancer tissue.The TME consists of different components such as, epithelial cells, myofibroblasts and immune cells.(2) Overview of cancerassociated changes.The chronic inflammatory response promotes cell division and repair and creates an environment that provokes cancer growth and development.

Table 1
List of naturally occurring and synthetic small molecules used to target inflammatory signaling pathways in cancer treatment.
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Table 2
List of nanoparticles used in cancer therapy targeting inflammatory pathways.