REFERENCES
2. Rini BI, Battle D, Figlin RA, et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J Immunother Cancer. 2019;7:354.
3. Doroshow DB, Sanmamed MF, Hastings K, et al. Immunotherapy in non-small cell lung cancer: facts and hopes. Clin Cancer Res. 2019;25:4592-602.
4. Huuhtanen J, Kasanen H, Peltola K, et al. Single-cell characterization of anti-LAG-3 and anti-PD-1 combination treatment in patients with melanoma. J Clin Invest. 2023;133:e164809.
5. Wang F, Fu K, Wang Y, et al. Small-molecule agents for cancer immunotherapy. Acta Pharm Sin B. 2024;14:905-52.
6. Huang Q, Wu X, Wang Z, et al. The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell. 2022;185:4049-66.e25.
7. Molodtsov AK, Khatwani N, Vella JL, et al. Resident memory CD8+ T cells in regional lymph nodes mediate immunity to metastatic melanoma. Immunity. 2021;54:2117-32.e7.
8. Asrir A, Tardiveau C, Coudert J, et al. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell. 2022;40:318-34.e9.
9. von Renesse J, Lin MC, Ho PC. Tumor-draining lymph nodes - friend or foe during immune checkpoint therapy? Trends Cancer. 2025;11:676-90.
10. du Bois H, Heim TA, Lund AW. Tumor-draining lymph nodes: at the crossroads of metastasis and immunity. Sci Immunol. 2021;6:eabg3551.
11. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336-47.
12. Zhang X, Schwartz JCD, Guo X, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004;20:337-47.
13. Achleitner A, Clark ME, Bienzle D. T-regulatory cells infected with feline immunodeficiency virus up-regulate programmed death-1 (PD-1). Vet Immunol Immunopathol. 2011;143:307-13.
14. Wang Z, Wu X. Study and analysis of antitumor resistance mechanism of PD1/PD-L1 immune checkpoint blocker. Cancer Med. 2020;9:8086-121.
15. Kubli SP, Berger T, Araujo DV, Siu LL, Mak TW. Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov. 2021;20:899-919.
16. Kluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer. 2020;8:e000398.
17. Dovedi SJ, Cheadle EJ, Popple AL, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin Cancer Res. 2017;23:5514-26.
18. Gabrielson A, Wu Y, Wang H, et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res. 2016;4:419-30.
19. Jerby-Arnon L, Shah P, Cuoco MS, et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell. 2018;175:984-97.e24.
20. Zhou M, Kim WY. Viewing RCC with a DNA methylation lens enhances understanding of ICI resistance. Clin Cancer Res. 2023;29:1170-2.
21. Jiang P, Gu S, Pan D, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24:1550-8.
22. Sun D, Liu J, Zhou H, et al. Classification of tumor immune microenvironment according to programmed death-ligand 1 expression and immune infiltration predicts response to immunotherapy plus chemotherapy in advanced patients with NSCLC. J Thorac Oncol. 2023;18:869-81.
23. Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541-50.
24. Vesely MD, Zhang T, Chen L. Resistance mechanisms to anti-PD cancer immunotherapy. Annu Rev Immunol. 2022;40:45-74.
25. Kim TK, Vandsemb EN, Herbst RS, Chen L. Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities. Nat Rev Drug Discov. 2022;21:529-40.
26. Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348:74-80.
27. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321-30.
28. Kim TK, Herbst RS, Chen L. Defining and understanding adaptive resistance in cancer immunotherapy. Trends Immunol. 2018;39:624-31.
29. Ren D, Hua Y, Yu B, et al. Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy. Mol Cancer. 2020;19:19.
30. Salem A, Alotaibi M, Mroueh R, Basheer HA, Afarinkia K. CCR7 as a therapeutic target in cancer. Biochim Biophys Acta Rev Cancer. 2021;1875:188499.
31. Schlechter BL, Stebbing J. CCR5 and CCL5 in metastatic colorectal cancer. J Immunother Cancer. 2024;12:e008722.
32. Liu C, Zheng S, Wang Z, et al. KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer. Cancer Commun. 2022;42:828-47.
33. Chow MT, Ozga AJ, Servis RL, et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity. 2019;50:1498-512.e5.
34. Neubert NJ, Schmittnaegel M, Bordry N, et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci Transl Med. 2018;10:eaan3311.
35. Sun Y, Chen W, Torphy RJ, et al. Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy. Sci Transl Med. 2021;13:eabc8922.
36. Anandappa AJ, Wu CJ, Ott PA. Directing traffic: how to effectively drive T cells into tumors. Cancer Discov. 2020;10:185-97.
37. Quan Y, He J, Zou Q, et al. Low molecular weight heparin synergistically enhances the efficacy of adoptive and anti-PD-1-based immunotherapy by increasing lymphocyte infiltration in colorectal cancer. J Immunother Cancer. 2023;11:e007080.
38. Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell. 2020;37:443-55.
39. Trujillo JA, Luke JJ, Zha Y, et al. Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma. J Immunother Cancer. 2019;7:295.
40. van Weverwijk A, de Visser KE. Mechanisms driving the immunoregulatory function of cancer cells. Nat Rev Cancer. 2023;23:193-215.
41. Martin CJ, Datta A, Littlefield C, et al. Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci Transl Med. 2020;12:eaay8456.
42. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019;176:1248-64.
43. Cantallops Vilà P, Ravichandra A, Agirre Lizaso A, Perugorria MJ, Affò S. Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology. 2024;79:941-58.
44. Lee CJ, Jang TY, Jeon SE, et al. The dysadherin/MMP9 axis modifies the extracellular matrix to accelerate colorectal cancer progression. Nat Commun. 2024;15:10422.
45. Ford K, Hanley CJ, Mellone M, et al. NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res. 2020;80:1846-60.
46. Cascone T, McKenzie JA, Mbofung RM, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 2018;27:977-87.e4.
47. Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022;40:201-18.e9.
48. Heuser C, Renner K, Kreutz M, Gattinoni L. Targeting lactate metabolism for cancer immunotherapy - a matter of precision. Semin Cancer Biol. 2023;88:32-45.
49. Zhang T, Yu W, Cheng X, et al. Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity. Sci Immunol. 2024;9:eadh2334.
51. Ringel AE, Drijvers JM, Baker GJ, et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell. 2020;183:1848-66.e26.
52. Fairfax BP, Taylor CA, Watson RA, et al. Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma. Nat Med. 2020;26:193-9.
53. Griffiths JI, Wallet P, Pflieger LT, et al. Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell interactions in patients during immunotherapy. Proc Natl Acad Sci U S A. 2020;117:16072-82.
54. Zhang F, Bai H, Gao R, et al. Dynamics of peripheral T cell clones during PD-1 blockade in non-small cell lung cancer. Cancer Immunol Immunother. 2020;69:2599-611.
55. Wu TD, Madireddi S, de Almeida PE, et al. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature. 2020;579:274-8.
56. Hudson D, Fernandes RA, Basham M, Ogg G, Koohy H. Can we predict T cell specificity with digital biology and machine learning? Nat Rev Immunol. 2023;23:511-21.
57. Kolumam GA, Thomas S, Thompson LJ, Sprent J, Murali-Krishna K. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med. 2005;202:637-50.
58. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707-23.
59. Rosenthal R, Cadieux EL, Salgado R, et al; TRACERx consortium. Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019;567:479-85.
60. Verdegaal EME, de Miranda NFCC, Visser M, et al. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature. 2016;536:91-5.
61. Wang X, Lamberti G, Di Federico A, et al. Tumor mutational burden for the prediction of PD-(L)1 blockade efficacy in cancer: challenges and opportunities. Ann Oncol. 2024;35:508-22.
62. Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30:44-56.
63. Hugo W, Zaretsky JM, Sun L, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165:35-44.
64. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.
65. Yarchoan M, Johnson BA 3rd, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. 2017;17:209-22.
66. Lv J, Zhou Y, Zhou N, et al. Epigenetic modification of CSDE1 locus dictates immune recognition of nascent tumorigenic cells. Sci Transl Med. 2023;15:eabq6024.
67. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409-13.
68. Escobar G, Tooley K, Oliveras JP, et al. Tumor immunogenicity dictates reliance on TCF1 in CD8+ T cells for response to immunotherapy. Cancer Cell. 2023;41:1662-79.e7.
69. Siddiqui I, Schaeuble K, Chennupati V, et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity. 2019;50:195-211.e10.
70. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486-99.
71. Sade-Feldman M, Jiao YJ, Chen JH, et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun. 2017;8:1136.
72. Yang K, Halima A, Chan TA. Antigen presentation in cancer - mechanisms and clinical implications for immunotherapy. Nat Rev Clin Oncol. 2023;20:604-23.
73. Gettinger S, Choi J, Hastings K, et al. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov. 2017;7:1420-35.
74. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819-29.
75. Fu L, Li S, Mei J, et al. BIRC2 blockade facilitates immunotherapy of hepatocellular carcinoma. Mol Cancer. 2025;24:113.
76. Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359:582-7.
77. Chang Y, Wu L. CapHLA: a comprehensive tool to predict peptide presentation and binding to HLA class I and class II. Brief Bioinform. 2024;26:bbae595.
78. Syn NL, Teng MWL, Mok TSK, Soo RA. De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol. 2017;18:e731-41.
79. Marijt KA, van Hall T. To TAP or not to TAP: alternative peptides for immunotherapy of cancer. Curr Opin Immunol. 2020;64:15-9.
80. von Locquenghien M, Rozalén C, Celià-Terrassa T. Interferons in cancer immunoediting: sculpting metastasis and immunotherapy response. J Clin Invest. 2021;131:143296.
81. Zhang X, Wang S, Zhu Y, et al. Double-edged effects of interferons on the regulation of cancer-immunity cycle. Oncoimmunology. 2021;10:1929005.
82. Wawrzyniak P, Hartman ML. Dual role of interferon-gamma in the response of melanoma patients to immunotherapy with immune checkpoint inhibitors. Mol Cancer. 2025;24:89.
83. Hoekstra ME, Slagter M, Urbanus J, et al. Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment. Cancer Cell. 2024;42:157-67.e9.
84. Jacquelot N, Yamazaki T, Roberti MP, et al. Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade. Cell Res. 2019;29:846-61.
85. Jiang Z, Hsu JL, Li Y, Hortobagyi GN, Hung MC. Cancer cell metabolism bolsters immunotherapy resistance by promoting an immunosuppressive tumor microenvironment. Front Oncol. 2020;10:1197.
86. Garris CS, Arlauckas SP, Kohler RH, et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity. 2018;49:1148-61.e7.
87. Hu B, Yu M, Ma X, et al. IFNα potentiates anti-PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment. Cancer Discov. 2022;12:1718-41.
88. Acha-Sagredo A, Andrei P, Clayton K, et al. A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer. Cancer Cell. 2025;43:292-307.e7.
89. Boutsikou E, Domvri K, Hardavella G, Tsiouda D, Zarogoulidis K, Kontakiotis T. Tumour necrosis factor, interferon-gamma and interleukins as predictive markers of antiprogrammed cell-death protein-1 treatment in advanced non-small cell lung cancer: a pragmatic approach in clinical practice. Ther Adv Med Oncol. 2018;10:1758835918768238.
90. Benci JL, Johnson LR, Choa R, et al. Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell. 2019;178:933-48.e14.
91. Boukhaled GM, Gadalla R, Elsaesser HJ, et al. Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy. Nat Immunol. 2022;23:1273-83.
92. Müller MR, Rao A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol. 2010;10:645-56.
93. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993;362:758-61.
94. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019;37:457-95.
95. Cheng H, Ma K, Zhang L, Li G. The tumor microenvironment shapes the molecular characteristics of exhausted CD8+ T cells. Cancer Lett. 2021;506:55-66.
97. Utzschneider DT, Gabriel SS, Chisanga D, et al. Early precursor T cells establish and propagate T cell exhaustion in chronic infection. Nat Immunol. 2020;21:1256-66.
98. Giles JR, Globig AM, Kaech SM, Wherry EJ. CD8+ T cells in the cancer-immunity cycle. Immunity. 2023;56:2231-53.
99. Miller BC, Sen DR, Al Abosy R, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20:326-36.
100. Chow A, Perica K, Klebanoff CA, Wolchok JD. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol. 2022;19:775-90.
101. Lan X, Zebley CC, Youngblood B. Cellular and molecular waypoints along the path of T cell exhaustion. Sci Immunol. 2023;8:eadg3868.
102. Mortezaee K, Majidpoor J. Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1. Biomed Pharmacother. 2023;163:114824.
103. Shayan G, Srivastava R, Li J, Schmitt N, Kane LP, Ferris RL. Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer. Oncoimmunology. 2017;6:e1261779.
104. Ren X, Zhang L, Zhang Y, Li Z, Siemers N, Zhang Z. Insights gained from single-cell analysis of immune cells in the tumor microenvironment. Annu Rev Immunol. 2021;39:583-609.
105. Cillo AR, Cardello C, Shan F, et al. Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity. Cell. 2024;187:4373-88.e15.
106. Spolski R, Li P, Leonard WJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018;18:648-59.
107. Diab A, Tannir NM, Bentebibel SE, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 2020;10:1158-73.
108. Tsui C, Kretschmer L, Rapelius S, et al. MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature. 2022;609:354-60.
109. Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol. 2020;20:55-70.
110. Ikeda H, Kawase K, Nishi T, et al. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature. 2025;638:225-36.
111. Saha T, Dash C, Jayabalan R, et al. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat Nanotechnol. 2022;17:98-106.
112. Icard P, Shulman S, Farhat D, Steyaert JM, Alifano M, Lincet H. How the Warburg effect supports aggressiveness and drug resistance of cancer cells? Drug Resist Updat. 2018;38:1-11.
113. Wu H, Campillo Prados M, Vaeth M. Metabolic regulation of T cell exhaustion. Immune Discov. 2025;1:10005.
114. Lontos K, Wang Y, Joshi SK, et al. Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors. J Immunother Cancer. 2023;11:e006522.
115. Ma S, Dahabieh MS, Mann TH, et al. Nutrient-driven histone code determines exhausted CD8+ T cell fates. Science. 2025;387:eadj3020.
116. Wilfahrt D, Delgoffe GM. Metabolic waypoints during T cell differentiation. Nat Immunol. 2024;25:206-17.
117. Reina-Campos M, Scharping NE, Goldrath AW. CD8+ T cell metabolism in infection and cancer. Nat Rev Immunol. 2021;21:718-38.
118. Mondal A, Smith C, DuHadaway JB, et al. IDO1 is an integral mediator of inflammatory neovascularization. EBioMedicine. 2016;14:74-82.
119. Heeren AM, van Dijk I, Berry DRAI, et al. Indoleamine 2,3-dioxygenase expression pattern in the tumor microenvironment predicts clinical outcome in early stage cervical cancer. Front Immunol. 2018;9:1598.
120. Ladomersky E, Zhai L, Lenzen A, et al. IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma. Clin Cancer Res. 2018;24:2559-73.
121. Krähenbühl L, Goldinger SM, Mangana J, et al. A longitudinal analysis of IDO and PDL1 expression during immune- or targeted therapy in advanced melanoma. Neoplasia. 2018;20:218-25.
122. Forster M, Brana I, Pousa AL, et al. Eftilagimod alpha (Soluble LAG3 Protein) combined with pembrolizumab as second-line therapy for patients with metastatic head and neck squamous cell carcinoma. Clin Cancer Res. 2024;30:3726-34.
123. Bell HN, Huber AK, Singhal R, et al. Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer. Cell Metab. 2023;35:134-49.e6.
124. Pauken KE, Sammons MA, Odorizzi PM, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016;354:1160-5.
125. Belk JA, Daniel B, Satpathy AT. Epigenetic regulation of T cell exhaustion. Nat Immunol. 2022;23:848-60.
126. Belk JA, Yao W, Ly N, et al. Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence. Cancer Cell. 2022;40:768-86.e7.
127. Chen F, Qian WB, Chen ZH, Qian J, Luo C. T cell exhaustion methylation signature drives differential immune responses in glioblastoma. Discov Oncol. 2024;15:530.
128. Huang C, Ren S, Chen Y, et al. PD-L1 methylation restricts PD-L1/PD-1 interactions to control cancer immune surveillance. Sci Adv. 2023;9:eade4186.
129. Widschwendter M, Jones A, Evans I, et al; FORECEE (4C) Consortium. Epigenome-based cancer risk prediction: rationale, opportunities and challenges. Nat Rev Clin Oncol. 2018;15:292-309.
130. Yan X, Zhao Y, Liu Y, et al. Case Report: Low-dose decitabine plus anti-PD-1 inhibitor camrelizumab for previously treated advanced metastatic non-small cell lung cancer. Front Oncol. 2020;10:558572.
131. Jenkins E, Whitehead T, Fellermeyer M, Davis SJ, Sharma S. The current state and future of T-cell exhaustion research. Oxf Open Immunol. 2023;4:iqad006.
132. Franco F, Jaccard A, Romero P, Yu YR, Ho PC. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab. 2020;2:1001-12.
133. Tonnerre P, Wolski D, Subudhi S, et al. Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. Nat Immunol. 2021;22:1030-41.
134. Yates KB, Tonnerre P, Martin GE, et al. Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans. Nat Immunol. 2021;22:1020-9.
135. De Henau O, Rausch M, Winkler D, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016;539:443-7.
136. Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547:217-21.
137. Gangadhar TC, Schneider BJ, Bauer TM, et al. Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol. 2017;35:9014.
138. Fan L, Xia Y, Wang Y, et al. Gut microbiota bridges dietary nutrients and host immunity. Sci China Life Sci. 2023;66:2466-514.
139. Schneider E, O’Riordan KJ, Clarke G, Cryan JF. Feeding gut microbes to nourish the brain: unravelling the diet-microbiota-gut-brain axis. Nat Metab. 2024;6:1454-78.
140. Heintz-Buschart A, Wilmes P. Human gut microbiome: function matters. Trends Microbiol. 2018;26:563-74.
141. Li S, Zhu S, Yu J. The role of gut microbiota and metabolites in cancer chemotherapy. J Adv Res. 2024;64:223-35.
142. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97-103.
143. Simpson RC, Shanahan ER, Scolyer RA, Long GV. Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2023;20:697-715.
144. Fernandes MR, Aggarwal P, Costa RGF, Cole AM, Trinchieri G. Targeting the gut microbiota for cancer therapy. Nat Rev Cancer. 2022;22:703-22.
145. Wong SH, Kwong TNY, Wu CY, Yu J. Clinical applications of gut microbiota in cancer biology. Semin Cancer Biol. 2019;55:28-36.
146. Zhou CB, Zhou YL, Fang JY. Gut microbiota in cancer immune response and immunotherapy. Trends Cancer. 2021;7:647-60.
147. Wang T, Gnanaprakasam JNR, Chen X, et al. Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction. Nat Metab. 2020;2:635-47.
148. Xiu W, Chen Q, Wang Z, Wang J, Zhou Z. Microbiota-derived short chain fatty acid promotion of Amphiregulin expression by dendritic cells is regulated by GPR43 and Blimp-1. Biochem Biophys Res Commun. 2020;533:282-8.
149. Fiorucci S, Marchianò S, Urbani G, et al. Immunology of bile acids regulated receptors. Prog Lipid Res. 2024;95:101291.
150. Lu Y, Yuan X, Wang M, et al. Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies. J Hematol Oncol. 2022;15:47.
151. Luu M, Riester Z, Baldrich A, et al. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun. 2021;12:4077.
152. Yi M, Qin S, Chu Q, Wu K. The role of gut microbiota in immune checkpoint inhibitor therapy. Hepatobiliary Surg Nutr. 2018;7:481-3.
153. Yi M, Yu S, Qin S, et al. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J Hematol Oncol. 2018;11:47.
154. Wang T, Zheng N, Luo Q, et al. Probiotics Lactobacillus reuteri abrogates immune checkpoint blockade-associated colitis by inhibiting group 3 innate lymphoid cells. Front Immunol. 2019;10:1235.
155. Wang S, Xu B, Zhang Y, et al. The role of intestinal flora on tumorigenesis, progression, and the efficacy of PD-1/PD-L1 antibodies in colorectal cancer. Cancer Biol Med. 2023;21:65-82.
156. Park JS, Gazzaniga FS, Wu M, et al. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance. Nature. 2023;617:377-85.
157. Gao Y, Bi W, Wu X, Zhu X, Luo Y. [Bacterial resistance influences intestinal flora and host immune regulation]. Chin J Biotechnol. 2018;34:1259-69.
158. da Silva Souza D, Barbosa BV, Ferreira IN, et al. The relationship between gut microbiota and immune system health. REASE. 2023;9:1173-83. (in Portuguese).
159. Hadi DK, Baines KJ, Jabbarizadeh B, et al. Improved survival in advanced melanoma patients treated with fecal microbiota transplantation using healthy donor stool in combination with anti-PD1: final results of the MIMic phase 1 trial. J Immunother Cancer. 2025;13:e012659.
160. Davar D, Dzutsev AK, McCulloch JA, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371:595-602.
161. Routy B, Lenehan JG, Miller WH Jr, et al. Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nat Med. 2023;29:2121-32.
162. Delclaux I, Ventre KS, Jones D, Lund AW. The tumor-draining lymph node as a reservoir for systemic immune surveillance. Trends Cancer. 2024;10:28-37.
163. Dammeijer F, van Gulijk M, Mulder EE, et al. The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes. Cancer Cell. 2020;38:685-700.e8.
164. Cruz de Casas P, Knöpper K, Dey Sarkar R, Kastenmüller W. Same yet different - how lymph node heterogeneity affects immune responses. Nat Rev Immunol. 2024;24:358-74.
165. Blanchard L, Girard JP. High endothelial venules (HEVs) in immunity, inflammation and cancer. Angiogenesis. 2021;24:719-53.
166. Vella G, Hua Y, Bergers G. High endothelial venules in cancer: regulation, function, and therapeutic implication. Cancer Cell. 2023;41:527-45.
167. Breslin JW. Lymphatic clearance and pump function. Cold Spring Harb Perspect Med. 2023;13:a041187.
168. Saddawi-Konefka R, Schokrpur S, Gutkind JS. Let it be: preserving tumor-draining lymph nodes in the era of immuno-oncology. Cancer Cell. 2024;42:930-3.
169. Tian W, Wei W, Qin G, et al. Lymphocyte homing and recirculation with tumor tertiary lymphoid structure formation: predictions for successful cancer immunotherapy. Front Immunol. 2024;15:1403578.
170. Lee CYC, Kennedy BC, Richoz N, et al. Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity. Nat Commun. 2024;15:682.
171. Alanko J, Uçar MC, Canigova N, et al. CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. Sci Immunol. 2023;8:eadc9584.
172. Garcia-Seyda N, Song S, Seveau de Noray V, et al. Naive T lymphocytes chemotax long distance to CCL21 but not to a source of bioactive S1P. iScience. 2023;26:107695.
173. Gérard A, Cope AP, Kemper C, Alon R, Köchl R. LFA-1 in T cell priming, differentiation, and effector functions. Trends Immunol. 2021;42:706-22.
174. Förster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008;8:362-71.
175. Kozai M, Kubo Y, Katakai T, et al. Essential role of CCL21 in establishment of central self-tolerance in T cells. J Exp Med. 2017;214:1925-35.
176. Takeda A, Salmi M, Jalkanen S. Lymph node lymphatic endothelial cells as multifaceted gatekeepers in the immune system. Trends Immunol. 2023;44:72-86.
177. Mirsky HP, Miller MJ, Linderman JJ, Kirschner DE. Systems biology approaches for understanding cellular mechanisms of immunity in lymph nodes during infection. J Theor Biol. 2011;287:160-70.
178. Acton SE, Farrugia AJ, Astarita JL, et al. Dendritic cells control fibroblastic reticular network tension and lymph node expansion. Nature. 2014;514:498-502.
179. Ruhland MK, Roberts EW, Cai E, et al. Visualizing synaptic transfer of tumor antigens among dendritic cells. Cancer Cell. 2020;37:786-99.e5.
180. Calzada-Fraile D, Iborra S, Ramírez-Huesca M, et al. Immune synapse formation promotes lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8+ T cells. Nat Commun. 2023;14:6772.
181. Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol. 2020;15:123-47.
182. Reticker-Flynn NE, Zhang W, Belk JA, et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell. 2022;185:1924-42.e23.
183. Xu Q, Chu J, Hu Q, et al. The role and clinical significance of tumor-draining lymph nodes in tumor progression and immunotherapy. Crit Rev Oncol Hematol. 2025;212:104745.
184. Randolph GJ, Ivanov S, Zinselmeyer BH, Scallan JP. The lymphatic system: integral roles in immunity. Annu Rev Immunol. 2017;35:31-52.
185. Ran S, Montgomery KE. Macrophage-mediated lymphangiogenesis: the emerging role of macrophages as lymphatic endothelial progenitors. Cancers. 2012;4:618-57.
186. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10.
187. Prokhnevska N, Cardenas MA, Valanparambil RM, et al. CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor. Immunity. 2023;56:107-24.e5.
188. Druzd D, Matveeva O, Ince L, et al. Lymphocyte circadian clocks control lymph node trafficking and adaptive immune responses. Immunity. 2017;46:120-32.
189. Reticker-Flynn NE, Engleman EG. Lymph nodes: at the intersection of cancer treatment and progression. Trends Cell Biol. 2023;33:1021-34.
190. Ugur M, Labios RJ, Fenton C, et al. Lymph node medulla regulates the spatiotemporal unfolding of resident dendritic cell networks. Immunity. 2023;56:1778-93.e10.
191. Martin-Almedina S, Mortimer PS, Ostergaard P. Development and physiological functions of the lymphatic system: insights from human genetic studies of primary lymphedema. Physiol Rev. 2021;101:1809-71.
192. Sokol CL, Camire RB, Jones MC, Luster AD. The chemokine receptor CCR8 promotes the migration of dendritic cells into the lymph node parenchyma to initiate the allergic immune response. Immunity. 2018;49:449-63.e6.
193. Okada N, Mori N, Koretomo R, et al. Augmentation of the migratory ability of DC-based vaccine into regional lymph nodes by efficient CCR7 gene transduction. Gene Ther. 2005;12:129-39.
194. Sun M, Gu P, Yang Y, et al. Mesoporous silica nanoparticles inflame tumors to overcome anti-PD-1 resistance through TLR4-NFκB axis. J Immunother Cancer. 2021;9:e002508.
195. Wang L, He Y, He T, et al. Lymph node-targeted immune-activation mediated by imiquimod-loaded mesoporous polydopamine based-nanocarriers. Biomaterials. 2020;255:120208.
196. Dasoveanu DC, Park HJ, Ly CL, et al. Lymph node stromal CCL2 limits antibody responses. Sci Immunol. 2020;5:eaaw0693.
197. Gillot L, Baudin L, Rouaud L, Kridelka F, Noël A. The pre-metastatic niche in lymph nodes: formation and characteristics. Cell Mol Life Sci. 2021;78:5987-6002.
198. Louie DAP, Liao S. Lymph node subcapsular sinus macrophages as the frontline of lymphatic immune defense. Front Immunol. 2019;10:347.
199. Su H, Wang Y, Khan S, et al. Immunotherapy shapes B-cell receptor repertoire to induce anti-tumor antibodies production in colon and lung cancer. Genome Instab Dis. 2024;5:183-96.
200. Zhang Y, Garcia-Ibanez L, Ulbricht C, et al. Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift. Nat Commun. 2022;13:2460.
201. Lamorte S, Quevedo R, Jin R, et al. Lymph node macrophages drive immune tolerance and resistance to cancer therapy by induction of the immune-regulatory cytokine IL-33. Cancer Cell. 2025;43:955-69.e10.
202. Dieterich LC, Detmar M. Tumor lymphangiogenesis and new drug development. Adv Drug Deliv Rev. 2016;99:148-60.
203. Ji RC. Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis. Cell Mol Life Sci. 2012;69:897-914.
204. Gardenier JC, Hespe GE, Kataru RP, et al. Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema. JCI Insight. 2016;1:e84095.
205. Zhang Y, Zhang C, Li L, et al. Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization. Cell Death Dis. 2021;12:109.
206. Liu P, Ding P, Sun C, et al. Lymphangiogenesis in gastric cancer: function and mechanism. Eur J Med Res. 2023;28:405.
207. Blass E, Ott PA. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat Rev Clin Oncol. 2021;18:215-29.
208. Xi X, Zhang L, Lu G, Gao X, Wei W, Ma G. Lymph node-targeting nanovaccine through antigen-CpG self-assembly potentiates cytotoxic T cell activation. J Immunol Res. 2018;2018:3714960.
209. Thomas SN, Vokali E, Lund AW, Hubbell JA, Swartz MA. Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response. Biomaterials. 2014;35:814-24.
210. Chu Y, Qian L, Ke Y, et al. Lymph node-targeted neoantigen nanovaccines potentiate anti-tumor immune responses of post-surgical melanoma. J Nanobiotechnology. 2022;20:190.
211. Chen J, Ye Z, Huang C, et al. Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response. Proc Natl Acad Sci U S A. 2022;119:e2207841119.
212. Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther. 2023;8:235.
213. Ni L. Potential mechanisms of cancer stem-like progenitor T-cell bio-behaviours. Clin Transl Med. 2024;14:e1817.
214. Rahim MK, Okholm TLH, Jones KB, et al. Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. 2023;186:1127-43.e18.
215. Kang TG, Lan X, Mi T, et al. Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy. Science. 2024;386:eadl4492.
216. Chen Z, Ji Z, Ngiow SF, et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity. 2019;51:840-55.e5.
217. Im SJ, Konieczny BT, Hudson WH, Masopust D, Ahmed R. PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection. Proc Natl Acad Sci U S A. 2020;117:4292-9.
218. Brummelman J, Mazza EMC, Alvisi G, et al. High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors. J Exp Med. 2018;215:2520-35.
219. Sade-Feldman M, Yizhak K, Bjorgaard SL, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell. 2018;175:998-1013.e20.
220. Xiong D, Yu H, Sun ZJ. Unlocking T cell exhaustion: insights and implications for CAR-T cell therapy. Acta Pharm Sin B. 2024;14:3416-31.
221. Lee M, Im SK, Baek S, et al. rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors. J Immunother Cancer. 2024;12:e008001.
222. Lee J, Lee K, Bae H, et al. IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation. Front Immunol. 2023;14:1117092.
223. Li X, Li Y, Dong L, et al. Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models. J Clin Invest. 2023;133:e165673.
224. Duraiswamy J, Turrini R, Minasyan A, et al. Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation. Cancer Cell. 2021;39:1623-42.e20.
225. Woroniecka KI, Rhodin KE, Dechant C, et al. 4-1BB agonism averts TIL exhaustion and licenses PD-1 blockade in glioblastoma and other intracranial cancers. Clin Cancer Res. 2020;26:1349-58.
226. Mullard A. FDA approves first tumour-infiltrating lymphocyte (TIL) therapy, bolstering hopes for cell therapies in solid cancers. Nat Rev Drug Discov. 2024;23:238.
227. Hu W, Bian Y, Ji H. TIL Therapy in lung cancer: current progress and perspectives. Adv Sci. 2024;11:e2409356.
228. Creelan B, Wang C, Teer J, et al. Abstract CT056: Durable complete responses to adoptive cell transfer using tumor infiltrating lymphocytes (TIL) in non-small cell lung cancer (NSCLC): a phase I trial. Cancer Res. 2020;80:CT056.
229. Tran E, Robbins PF, Lu YC, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med. 2016;375:2255-62.
230. Wang S, Sun J, Chen K, et al. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med. 2021;19:140.
231. Klobuch S, Seijkens TTP, Schumacher TN, Haanen JBAG. Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma. Nat Rev Clin Oncol. 2024;21:173-84.
232. Huang H, Nie CP, Liu XF, et al. Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer. J Clin Invest. 2022;132:e157726.
233. van den Berg JH, Heemskerk B, van Rooij N, et al. Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up. J Immunother Cancer. 2020;8:e000848.
234. Okamura K, Nagayama S, Tate T, Chan HT, Kiyotani K, Nakamura Y. Lymphocytes in tumor-draining lymph nodes co-cultured with autologous tumor cells for adoptive cell therapy. J Transl Med. 2022;20:241.
235. Zhen YH, Liu XH, Yang Y, et al. Phase I/II study of adjuvant immunotherapy with sentinel lymph node T lymphocytes in patients with colorectal cancer. Cancer Immunol Immunother. 2015;64:1083-93.








