Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy

Cancer immunotherapy has become an established therapeutic paradigm in oncologic therapy, but its therapeutic efficacy remains unsatisfactory in the majority of cancer patients. Accumulating evidence demonstrates that the metabolically hostile tumor microenvironment (TME), characterized by acidity, deprivation of oxygen and nutrients, and accumulation of immunosuppressive metabolites, promotes the dysfunction of tumor-infiltrating immune cells (TIICs) and thereby compromises the effectiveness of immunotherapy. This indicates the potential role of tumor metabolic intervention in the reinvigoration of antitumor immunity. With the merits of multiple drug codelivery, cell and organelle-specific targeting, controlled drug release, and multimodal therapy, tumor metabolism-rewriting nanomedicines have recently emerged as an attractive strategy to strengthen antitumor immune responses. This review summarizes the current progress in the development of multifunctional tumor metabolism-rewriting nanomedicines for evoking antitumor immunity. A special focus is placed on how these nanomedicines reinvigorate innate or adaptive antitumor immunity by regulating glucose metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism at the tumor site. Finally, the prospects and challenges in this emerging field are discussed.

The aim of this review is to offer readers an overview of nano-enabled interven�ons in tumor metabolisms of amino acid, glucose, lipid, and nucleo�de for enhanced immunotherapy.We hope this review ar�cle would assist readers in gaining a comprehensive understanding of this emerging field.
According to the reviewer's comment, an informa�ve descrip�on of how metabolites regulate tumor immunity is now added in the revised manuscript.Specific informa�on is atached below for your convenience in reading: Page 3, Paragraph 2, Line 4: "Specifically, abnormal tumor metabolisms of glucose, amino acid, lipid, and nucleo�de lead to the intratumoral produc�on and accumula�on of immunosuppressive/cytotoxic metabolites, resul�ng in tumor immune evasion by promo�ng the dysfunc�on and apoptosis of tumor-infiltra�ng immune cells (TIICs).17,19-22 For example, tumor glycolysis produces lactate as a byproduct, which can enhance immune tolerance by upregula�ng the expression of programmed death-ligand 1 (PD-L1) in tumorassociated macrophages (TAMs) and directly impairing the prolifera�on and cytoly�c ac�vity of CD8+ effector T (Teff) cells.23-24As an amino acid metabolite, kynurenine (Kyn) not only facilitates the differen�a�on of CD4+ T cells into regulatory T cells (Tregs) but also elevates the expression of programmed cell death protein 1 (PD-1) in CD8+ T cells.25-26Prostaglandin E2 (PGE2), produced via lipid metabolism, plays a cri�cal role in facilita�ng tumor immune evasion by influencing the func�on of T lymphocytes, myeloid-derived suppressor cells (MDSCs), and dendri�c cells (DCs).27Adenosine generated by hydrolysis of adenosine triphosphate (ATP) ac�vates the immunosuppressive adenosine receptor signaling and ul�mately inhibits the ac�va�on, prolifera�on, and survival of T cells and B cells.28" 2. Glycolysis plays different roles in cancer cells and immune cells.It is suggested that the authors should discuss the pros and cons of glycolysis-targe�ng therapy.
Response: Thank you for poin�ng this out and your good sugges�on.
According to the reviewer's comment, the discussions about the pros and cons of glycolysis-targe�ng therapy are now added in the revised manuscript.Specific informa�on is atached below for your convenience in reading.3. The authors summarized many research cases on this topic but the descrip�on is superficial, lacking insigh�ul analysis and discussion.
Response: Thank you for your valuable sugges�on.
According to the reviewer's comment, more analysis and discussions have been added in the revised manuscript.Specific informa�on is atached below for your convenience in reading.
Page 10, Paragraph 1, Line 16: "Therefore, the concurrent upregula�on of mitochondrial OXPHOS and downregula�on of glycolysis in tumor cells provides a promising strategy to mi�gate the immunosuppressive TMME.In this regard, Jia et al. developed GSH and pH dual-responsive mPEG-PLA-PHis-ss-PEI polyplexes (DRP/Res/siP) encapsula�ng PD-L1 siRNA and resveratrol (Table 2).70This nanomedicine promoted ICB-based immunotherapy by simultaneously regula�ng glycolysis and OXPHOS of tumor cells.Notably, the conver�ble non-electrosta�c interac�ons between the PHis block of the copolymer and siRNA facilitated the synchronized release of PD-L1 siRNA and resveratrol.This phenomenon was ascribed to the destabiliza�on of siRNA polyplexes in the intracellular acidic and reduc�ve environment.The released resveratrol inhibited the glycolysis and upregulated OXPHOS in cancer cells through PKM2 downregula�on and ac�va�on of adenosine monophosphate (AMP)-ac�vated protein kinase (AMPK).In vivo an�-tumor experiments demonstrated that upregula�on of mitochondrial OXPHOS pathways not only promoted the tumor infiltra�on of CD8+/CD4+ T lymphocytes and IFN-γ secre�on but also suppressed Treg cells and MDSCs.This nanomedicine reprogrammed the glucose metabolism in tumor cells, and in conjunc�on with PD-L1 silencing, promoted the forma�on of a less immune-suppressive TME.However, the efficacy of this nanomedicine would be influenced by the heterogenic GSH levels and the tumor acidity.
Page 12, Paragraph 1, Line 10: "The highly expressed pyruvate dehydrogenase kinase 1 (PDK1) in mitochondria plays a crucial role in regula�ng tumor glycolysis, represen�ng a promising target for glycolysis inhibi�on in cancer cells.76The therapeu�c efficacy of dichloroacetate (DCA, a PDK1 inhibitor) was hindered by limited cellular uptake and inadequate mitochondrial localiza�on.To circumvent these limita�ons, a triphenylphosphonium (TPP) ca�on-modified nanoassembly (T-Mito-DCA-NP) was developed to achieve mitochondrion-targeted delivery of DCA, leading to a reprogrammed immunosuppressive TMME (Table 2).77"Page 16, Paragraph 2, Line 13: "Of note, the byproduct H2O2 produced by LOX-mediated lactate metabolism can react with a chemiluminescence reagent (bis[2,4,5-trichloro-6-(pentyloxycarbonyl) phenyl] oxalate, CPPO), subsequently releasing energy capable of ac�va�ng the photosensi�zer."Page 17, Paragraph 1, Line 13: "In contrast to exogenous laser source-dependent PDT, this approach circumvents the atenuated PDT efficacy resul�ng from inadequate laser penetra�on within tumor �ssues."Page 17, Paragraph 1, Line 25: "Such inorganic nanomaterials with enzyma�c cataly�c ac�vity offer dis�nct advantages over enzymemediated lactate metabolism due to their ability to func�on efficiently under harsh condi�ons."Page 21, Paragraph 1, Line 24: "Despite numerous advantages of OMVs as drug delivery carriers, their inherent immunogenic proper�es lead to accelerated immune clearance in blood circula�on, consequently compromising the efficacy of drug delivery systems aimed at tumor targe�ng.""Direct intratumoral administra�on of highly hydrophilic Arg faces several obstacles, including enzyma�c degrada�on and rapid outward diffusion of the compound in TME.These factors can substan�ally decrease the concentra�on of Arg, consequently compromising its therapeu�c effec�veness at the tumor site.141"Page 45, Paragraph 2, Line 3: "The suppression of acetyl-CoA acetyltransferase 1 (ACAT1, a cholesterol-esterifica�on enzyme) with avasimibe (AVA) can enhance the tumoricidal ac�vity of Teff by promo�ng TCR clustering.166However, the efficacy of AVA was constrained by the dis�nct pharmacokine�cs and biodistribu�on profiles between AVA and T cells.To overcome this obstacle, a "backpacking strategy" was developed to regulate cholesterol metabolism in T cells and boost T cell-based immunotherapy against melanoma (Figure 11A, Table 4).167"Page 46, Paragraph 1, Line 8: The limited penetra�on of tumor metabolism-regula�ng nanomedicine within tumor �ssues significantly undermines their therapeu�c efficacy."Page 54, Paragraph 3, Line 1: "In recent years, there has been growing interest in u�lizing the second near-infrared (NIR-II) light (1000-1500 nm) for PTT due to the enhanced �ssue penetra�on capacity and higher permissible energy for skin irradia�on." Page 55, Paragraph 1, Line 11: "However, the SP backbone caused an aggrega�on-caused quenching (ACQ) effect owing to intermolecular interac�ons (predominantly π-π stacking).This phenomenon may hinder the u�liza�on of these materials in cancer phototheranos�cs." 4. To target the tumor metabolism (e.g., various cell types in the TME), the cell type-specific delivery strategies should be provided with detailed analysis.
Response: Thank you for poin�ng this out and your good sugges�on.
According to the reviewer's comment, the cell type-specific delivery strategies have been provided with detailed analysis in the main text.Specific informa�on is atached below for your convenience in reading."This nanosystem first released PTX in response to acidic TME, and the remaining mannose-modified OMVs encapsula�ng Redd1 siRNA were selec�vely internalized by M2-like TAMs owing to specific interac�ons between CD206 and mannose (Figure 4E)."Page 47, Paragraph 1, Line 1: "Nevertheless, the challenge persists in achieving the upregula�on of FA catabolism in TIICs while avoiding the favorable metabolic regula�on in cancer cells.To circumvent this problem, a T-cell-targe�ng nanomedicine (aCD3/F/ANs) was fabricated by encapsula�ng fenofibrate (a lipid metabolism-ac�va�ng drug) in an�-CD3 ef(ab´)2 fragment-modified NPs (Figure 11D, Table 4).174" 5.It is suggested to briefly introduce the pipelines of drug development.
Response: Thank you for poin�ng this out and your sugges�on.
According to the reviewer's comment, the table (Table 1.Exemplary clinical trials exploring the combina�on of tumor metabolic interven�ons with immune-checkpoint inhibitors (ICIs)) summarizing the pipelines of drug development is now added in the revised manuscript (Page 6 to Page 8).
In addi�on, we briefly introduced the pipelines of drug development in the main text.Specific informa�on is atached below for your convenience in reading.
Response: Thank you for poin�ng this out and your sugges�on.
According to the reviewer's comment, the discussions on the challenges in this field have been added in the revised manuscript.Specific informa�on is atached below for your convenience in reading.
Page 59, Paragraph 2, Line 1: "Despite the fact that this emerging field has achieved significant advances, several major challenges need to be overcome before successful clinical transla�on can occur.Firstly, increasing evidence demonstrates that tumor cells can develop compensatory metabolic pathways, enabling them to acquire resistance against the single interven�on targe�ng tumor metabolism.192Therefore, simultaneously targe�ng mul�ple cellular metabolisms in cancer cells presents a robust approach to accomplish efficacious interven�on in tumor metabolism.Secondly, it is s�ll difficult to develop nanomedicine that can selec�vely target tumor metabolic ac�vi�es while minimizing unintended effects on TIICs.This is primarily atributed to the substan�al similari�es in cellular metabolic processes between cancer cells and TIICs.193The endeavor to iden�fy specific cell surface markers that can differen�ate cancer cells from TIICs will contribute to the design of precision nanomedicines that can selec�vely target cancer cells while sparing TIICs.Addi�onally, endogenous s�mulus-responsive strategies can be implemented to selec�vely liberate metabolic regulators exclusively within malignant cancer cells.Thirdly, the spa�altemporal heterogeneity of tumors impedes the effec�veness of tumor metabolism interven�on.Different regions of tumors may have dis�nct metabolic characteris�cs, and the cellular metabolic pathways in the TME are dynamic and constantly evolving at different stages of tumor development and progression.194-195Combina�on therapies that integrate nano-enabled metabolic interven�ons with other treatment modali�es, such as molecular-targeted therapy, immunotherapies, chemotherapy, and irradia�on, offer poten�al solu�ons to address these challenges.Fourthly, restricted accumula�on and penetra�on of nanomedicines 196 in tumor �ssues may compromise the therapeu�c effec�veness of tumor metabolism-regula�ng nanomedicines.The therapeu�c strategy combining stromal desmoplasia deple�on with TMME manipula�on has been proposed to improve the spa�al distribu�on of tumor metabolism-regula�ng nanomedicine.168However, the subop�mal spa�al distribu�on of these nanomedicines within tumor sites arises from the collec�ve influence of mul�ple factors, such as the interplay of inters��al fluid pressure (IFP), dysregulated vasculature networks, dense ECM, and solid stress within the TME.197To overcome these obstacles, more efforts are needed to develop tumor metabolism-regula�ng nanomedicines that could simultaneously regulate the tumor metabolism and the physically complex TME.

Response to Reviewer 2:
Comments: In this manuscript, the authors reviewed the progress in the development of nanomedicines for immunometabolic therapy against tumors.In par�cularly, recent research in nano-enabled interven�on of glucose, amino acid, lipid and nucleo�de metabolism in tumor microenvironment was well-summarized.This is a comprehensive review, and I believe it will be useful for those are working in the related fields.However, the current manuscript seems to be too long as an Outlook, and some minor revisions are s�ll needed.
Response: Thank you for your posi�ve assessment and encouragement.
1. Importantly, the authors are suggested to discuss the research examples more concisely, with less details regarding the experimental results, while more emphasis and comments on the design intelligence in the nanomedicine toward metabolic interven�on.
Response: Thank you for poin�ng this out and your sugges�on.
According to the reviewer's comment, discussions on research cases have been revised in the main text to provide more emphasis on the design intelligence in the nanomedicine toward metabolic interven�on.Specific informa�on is atached below for your convenience in reading.
Page 12, Paragraph 1, Line 10: "The highly expressed pyruvate dehydrogenase kinase 1 (PDK1) in mitochondria plays a crucial role in regula�ng tumor glycolysis, represen�ng a promising target for glycolysis inhibi�on in cancer cells.76The therapeu�c efficacy of dichloroacetate (DCA, a PDK1 inhibitor) was hindered by limited cellular uptake and inadequate mitochondrial localiza�on.To circumvent these limita�ons, a triphenylphosphonium (TPP) ca�on-modified nanoassembly (T-Mito-DCA-NP) was developed to achieve mitochondrion-targeted delivery of DCA, leading to a reprogrammed immunosuppressive TMME (Table 2).77""Notably, the lactoferrin (an iron-carrying protein) of the resultant nanomedicine selec�vely bound to the overexpressed low-density lipoprotein receptor-related protein 1 (LRP-1) on tumor vascular endothelial cells and tumor cells.In addi�on, the interac�on between mannose and its receptor (MR) allowed Man-LF NPs to target M2-like TAMs with MR overexpression."Page 10, Paragraph 1, Line 16: "Therefore, the concurrent upregula�on of mitochondrial OXPHOS and downregula�on of glycolysis in tumor cells provides a promising strategy to mi�gate the immunosuppressive TMME.In this regard, Jia et al. developed GSH and pH dual-responsive mPEG-PLA-PHis-ss-PEI polyplexes (DRP/Res/siP) encapsula�ng PD-L1 siRNA and resveratrol (Table 2).70This nanomedicine promoted ICB-based immunotherapy by simultaneously regula�ng glycolysis and OXPHOS of tumor cells.Notably, the conver�ble non-electrosta�c interac�ons between the PHis block of the copolymer and siRNA facilitated the synchronized release of PD-L1 siRNA and resveratrol.This phenomenon was ascribed to the destabiliza�on of siRNA polyplexes in the intracellular acidic and reduc�ve environment.The released resveratrol inhibited the glycolysis and upregulated OXPHOS in cancer cells through PKM2 downregula�on and ac�va�on of adenosine monophosphate (AMP)-ac�vated protein kinase (AMPK).In vivo an�-tumor experiments demonstrated that upregula�on of mitochondrial OXPHOS pathways not only promoted the tumor infiltra�on of CD8+/CD4+ T lymphocytes and IFN-γ secre�on, but also suppressed Treg cells and MDSCs.This nanomedicine reprogrammed the glucose metabolism in tumor cells, and in conjunc�on with PD-L1 silencing, promoted the forma�on of a less immune-suppressive TME.However, the efficacy of this nanomedicine would be influenced by the heterogenic GSH levels and the tumor acidity.
Page 21, Paragraph 1, Line 5: "Augmenta�on of cellular glycolysis levels represents an alterna�ve approach to induce the transforma�on of M2-like TAMs towards M1-like phenotypes.However, it remains a challenge to selec�vely deliver metabolic regulators to TAMs while avoiding favorable metabolic regula�on in malignant cells that u�lize glycolysis as an energy source."The suppression of acetyl-CoA acetyltransferase 1 (ACAT1, a cholesterol-esterifica�on enzyme) with avasimibe (AVA) can enhance the tumoricidal ac�vity of Teff by promo�ng TCR clustering.166However, the efficacy of AVA was constrained by the dis�nct pharmacokine�cs and biodistribu�on profiles between AVA and T cells.To overcome this obstacle, a "backpacking strategy" was developed to regulate cholesterol metabolism in T cells and boost T cell-based immunotherapy against melanoma (Figure 11A, Table 4).167"Page 47, Paragraph 1, Line 1: "Nevertheless, the challenge persists in achieving the upregula�on of FA catabolism in TIICs while avoiding the favorable metabolic regula�on in cancer cells.To circumvent this problem, a T-cell-targe�ng nanomedicine (aCD3/F/ANs) was fabricated by encapsula�ng fenofibrate (a lipid metabolism-ac�va�ng drug) in an�-CD3 ef(ab´)2 fragment-modified NPs (Figure 11D, Table 4).174"Page 55, Paragraph 1, Line 12: "However, SP backbone having NIR-II light-absorbing ability could give rise to an aggrega�on-caused quenching (ACQ) effect owing to intermolecular interac�ons (predominantly π-π stacking).This phenomenon substan�vely hinders the effec�ve u�liza�on of these materials in the field of cancer phototheranos�cs."Page 55, Paragraph 1, Line 17: "In the presence of high concentra�ons of H2O2 within tumor cells, CPT was ac�vated and released from CAT-NP, thereby promo�ng the release of TST and AZD4635 by inducing the disassembly of CAT-NP." 2. There is crosstalk between the tumor metabolic pathways of glucose, amino acid, lipid and nucleo�de, and such interplay between different pathways is suggested to be briefly discussed in the manuscript.In addi�on, are there any recent cases of using nanomedicine for dual-metabolism pathway regula�on?Response: Thank you for poin�ng this out and your good comment.
According to the reviewer's comment, the interplay between tumor metabolic pathways has ever been reported.The related content has been added in the revised manuscript.Two cases of using nanomedicine for dual-metabolism pathway regula�on have been included in the main text.Specific informa�on is atached below for your convenience in reading."In addi�on, there is a complex crosstalk between the metabolism of glucose, amino acids, lipids, and nucleo�des in TME.Typically, the metabolites from tumor glycolysis can serve as a prominent carbon source for lipid synthesis.198A beter and in-depth understanding on these intricate tumor metabolic profiles and molecular immune networks would iden�fy vulnerabili�es that can be targeted for therapeu�c interven�ons and promote the ra�onal design of nanotherapeu�cs for tumor immunometabolic therapy."Page 29, Paragraph 1, Line 16: "The TMME presents a highly complex milieu with the capability to impede TIIC func�onality through various mechanisms.As a result, simultaneous targe�ng of mul�ple metabolic pathways could exert a synergis�c effect and improve an�tumor immune responses.Recently, a nutrient par��oning nanoregulator (DMNPN) with GSH responsiveness and pH-triggered charge reversal proper�es was developed to concurrently inhibit glycolysis and glutamine metabolism in cancer cells (Table 3).125 DMNPN was prepared by loading glycolysis inhibitor LND into amino-func�onalized, disulfide-bonded mesoporous organosilica NPs (NH2-MONs).The surface of NH2-MONs was then coated with ca�onic PEI and poly(allylamine hydrochloride)-citraconic anhydride (PAH-cit), which not only facilitated loading of an�-glutaminase siRNA (siGLS) via electrosta�c interac�on but also prevented the premature release of LND.Upon arrival at tumor �ssues, the GSH-triggered degrada�on of NH2-MONs and pH-driven PAH-cit charge-reversal facilitated the release of LND and siGLS.Subsequent inhibi�on of glycolysis by LND and downregula�on of glutaminase expression by siGLS enabled the proper maintenance of nutrients necessary for T cells, by reducing the consump�on of glucose and glutamine from tumor cells."Page 33, Paragraph 1, Line 11: "The concurrent inhibi�on of cancer cell energy metabolism and mi�ga�on of Kyn-mediated tumor immune suppression presents a synergis�c strategy to enhance an�tumor immunity.In this regard, a nanoassembly, u�lizing a F127-coated prodrug dimer (LSD), was developed to concurrently inhibit glycolysis and IDO within tumor cells (Table 3).136The prodrug was synthesized by conjuga�ng LND and NLG919 through a disulfide bond.The high level of intracellular GSH in cancer cells facilitated the cleavage of disulfide bond, resul�ng in the release of LND and NLG919.Subsequently, the released LND impeded energy supply by inducing mitochondrial dysfunc�on and inhibi�ng glycolysis in tumor cells.Addi�onally, NLG919 inhibited Trp catabolism and mi�gated immunosuppressive TME by reducing the popula�on of Tregs at tumor sites.Notably, the disulfide bond-mediated GSH deple�on in cancer cells exacerbated intracellular oxida�ve stress and consequently induced ICD." 3. The word "rewri�ng" is frequently men�oned, and I don't know whether it is appropriate to use "rewri�ng metabolism" for all the examples.The authors beter provide a clear defini�on for this word in the manuscript.

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Paragraph 1, Line 6: "From this perspec�ve, the suppression of tumor glycolysis may serve as a targeted strategy to selec�vely eliminate tumor cells.Consequently, this interven�on would have low off-target effects, thereby offering a benefit over the non-selec�ve cytotoxicity frequently encountered with tradi�onal chemotherapy and radia�on therapy."Page 9, Paragraph 2, Line 3: "Hence, inhibi�on of tumor glycolysis presents a viable strategy to disrupt lactate-mediated immune suppression and promote an�tumor immunotherapy."Page 12, Paragraph 1, Line 3: "These results suggested that the pharmacological inhibi�on of tumor glycolysis could not only disrupt the energy produc�on in cancer cells but also enhance an�tumor immunity through decreased lactate produc�on and allevia�on of nutrient depriva�on in the TME."Page 12, Paragraph 1, Line 7: "Consequently, indiscriminately inhibi�ng cellular glycolysis at the tumor site may undermine the an�tumor func�on of TIICs."

Page 9 ,
Paragraph 2, Line 8: "Due to the specific recogni�on of FA and folate receptor (FR), the resultant nanomedicine exhibited excellent targe�ng ability toward FR-posi�ve cancer cells."Page 10, Paragraph 1, Line 8: "Notably, the lactoferrin (an iron-carrying protein) of the resultant nanomedicine selec�vely bound to the overexpressed low-density lipoprotein receptor-related protein 1 (LRP-1) on tumor vascular endothelial cells and tumor cells.In addi�on, the interac�on between mannose and mannose receptor (MR) allowed Man-LF NPs to target M2-like TAMs with MR overexpression.However, these approaches for inhibi�ng tumor glycolysis didn't consider the poten�al beneficial impact of mitochondrial OXPHOS."Page 11, Paragraph 2, Line 10: "The resultant nanodrugs targeted to the tumor site and entrapped in the TEM, which was achieved by the recogni�on of the an�-mesothelin an�body and the overexpressed mesothelin on the pancrea�c cancer cell membrane."Page 20, Paragraph 2, Line 12: "The resul�ng t-LRR exhibited a dual-targe�ng ability to both CT26 colon cancer cells and M2-like TAMs, through binding to PD-L1 or MR on the cells."Page 21, Paragraph 1, Line 5: "Augmenta�on of cellular glycolysis levels represents an alterna�ve approach to induce the transforma�on of M2-like TAMs towards M1-like phenotypes.However, it remains a challenge to selec�vely deliver metabolic regulators to TAMs while avoiding favorable metabolic regula�on in malignant cells that u�lize glycolysis as an energy source.The overexpression of MR (CD206) in TAMs offers poten�al for the development of TAMs-targeted drug delivery systems103."Page 21, Paragraph 1, Line 18: The overexpression of MR (CD206) in TAMs offers poten�al for the development of TAMs-targeted drug delivery systems103."Page 21, Paragraph 1, Line 18: "This nanosystem first released PTX in response to acidic TME, and the remaining mannose-modified OMVs encapsula�ng Redd1 siRNA were selec�vely internalized by M2-like TAMs owing to specific interac�ons between CD206 and mannose (Figure 4E)."Page 40, Paragraph 1, Line 21: "The deferoxamine mesylate (DFO)-induced disassembly of FeLPNPs triggered the release of luteolin, mi�gated the inflammatory responses induced by PTT, and inhibited tumor recurrence by reducing TNFα and IL-6 secre�on."