The tumor necrosis factor receptor superfamily in lung cancer immunotherapy: Therapeutic opportunities and challenges

Abstract

Immune checkpoint blockade has fundamentally reshaped the therapeutic landscape of lung cancer. However, durable clinical benefits remain restricted to a subset of patients. Members of the tumor necrosis factor receptor superfamily (TNFRSF) and their ligands represent a highly versatile class of immune regulators governing T cell activation, immune cell crosstalk, and tumor microenvironment remodeling. Unlike classical immune checkpoints, TNFRSF signaling exhibits pronounced functional plasticity, displaying immunostimulatory or immunosuppressive effects depending on cellular context, spatial organization, and disease stage. This duality complicates the clinical translation of TNFRSF-targeted strategies, despite compelling preclinical evidence and their relevance in immune-related toxicities and inflammatory disorders. In this review, we synthesize recent advances in understanding the context-dependent roles of key TNFRSF axes in lung cancer, focusing on their contributions to immune activation and escape and therapeutic resistance. We further discuss emerging technologies and rational combination strategies that may enable more precise and effective exploitation of TNFRSF pathways, aiming to clarify the opportunities and limitations of TNFRSF-based immunotherapy in lung cancer.

Keywords

immunotherapy / lung cancer / TNF receptors

References

[1] Vokes NI, Pan K, Le X. Efficacy of immunotherapy in oncogene-driven non-small-cell lung cancer. Ther Adv Med Oncol. 2023; 15:17588359231161409.

[2] Lui K, Cheung KK, Ng WW, Wang Y, Au DWH, Cho WC. The impact of genetic mutations on the efficacy of immunotherapies in lung cancer. Int J Mol Sci. 2024; 25:11954.

[3] Sun T, Chen Z, Wei K, Tang H. Research progress on predictive biomarkers of immunotherapy efficacy in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 2024; 27: 459-465.

[4] Dostert C, Grusdat M, Letellier E, Brenner D. The TNF family of ligands and receptors: communication modules in the immune system and beyond. Physiol Rev. 2019; 99: 115-160.

[5] Ababneh O, Nishizaki D, Kato S, Kurzrock R. Tumor necrosis factor superfamily signaling: life and death in cancer. Cancer Metastasis Rev. 2024; 43: 1137-1163.

[6] Mahmud SA, Manlove LS, Schmitz HM, et al. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol. 2014; 15: 473-481.

[7] Faustman D, Davis M. TNF receptor 2 pathway: drug target for autoimmune diseases. Nat Rev Drug Discov. 2010; 9: 482-493.

[8] Xu J. The role of tumor necrosis factor receptor superfamily in cancer: insights into oncogenesis, progression, and therapeutic strategies. NPJ Precis Oncol. 2025; 9:275.

[9] Cusick JK, Alhomsy Y, Wong S, et al. RELT stains prominently in B-cell lymphomas and binds the hematopoietic transcription factor MDFIC. Biochem Biophys Rep. 2020; 24:100868.

[10] Gui L, Wang Z, Lou W, et al. Comparative evaluation of antitumor effects of TNF superfamily costimulatory ligands delivered by mesenchymal stem cells. Int Immunopharmacol. 2024; 126:111249.

[11] So T, Lee SW, Croft M. Immune regulation and control of regulatory T cells by OX40 and 4-1BB. Cytokine Growth Factor Rev. 2008; 19: 253-262.

[12] Lagou S, Grapsa D, Syrigos N, Bamias G. The role of decoy receptor DcR3 in gastrointestinal malignancy. Cancer Diagn Prognosis. 2022; 2: 411-421.

[13] Porto DM, Costa GJ, Torres LC, Casarini DE. Immune checkpoint expression as prognostic biomarker candidates in non-small cell lung carcinoma patients. J Surg Oncol. 2024; 130: 919-928.

[14] Gorgulho J, Loosen SH, Masood R, et al. Soluble and EV-bound CD27 act as antagonistic biomarkers in patients with solid tumors undergoing immunotherapy. J Exp Clin Cancer Res. 2024; 43: 298.

[15] Khan M, Alteneder M, Reiter W, et al. Single-cell and chromatin accessibility profiling reveals regulatory programs of pathogenic Th2 cells in allergic asthma. Nat Commun. 2025; 16:2565.

[16] Sato A, Azuma M, Nagai H, et al. OX40 ligand-mannose-binding lectin fusion protein induces potent OX40 cosignaling in CD4(+) T cells. Biol Pharm Bull. 2022; 45: 1798-1804.

[17] Ward-Kavanagh LK, Lin WW, Sedy JR, Ware CF. The TNF receptor superfamily in co-stimulating and co-inhibitory responses. Immunity. 2016; 44: 1005-1019.

[18] Chen X, Subleski JJ, Hamano R, Howard OM, Wiltrout RH, Oppenheim JJ. Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood. Eur J Immunol. 2010; 40: 1099-1106.

[19] Michaelson JS, Wisniacki N, Burkly LC, Putterman C. Role of TWEAK in lupus nephritis: a bench-to-bedside review. J Autoimmun. 2012; 39: 130-142.

[20] Liu L, Wu Y, Ye K, Cai M, Zhuang G, Wang J. Antibody-targeted TNFRSF activation for cancer immunotherapy: the role of FcgammaRIIB cross-linking. Front Pharmacol. 2022; 13:924197.

[21] Ha YJ, Seul HJ, Lee JR. Ligation of CD40 receptor in human B lymphocytes triggers the 5-lipoxygenase pathway to produce reactive oxygen species and activate p38 MAPK. Exp Mol Med. 2011; 43: 101-110.

[22] Frankish J, Mukherjee D, Romano E, et al. The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapy. Front Immunol. 2023; 14:1160116.

[23] Zaitseva O, Hoffmann A, Otto C, Wajant H. Targeting fibroblast growth factor (FGF)-inducible 14 (Fn14) for tumor therapy. Front Pharmacol. 2022; 13:935086.

[24] Zhou Y, Qin X, Hu Q, et al. Cross-talk between disulfidptosis and immune check point genes defines the tumor microenvironment for the prediction of prognosis and immunotherapies in glioblastoma. Sci Rep. 2024; 14:3901.

[25] Papadakos SP, Chatzikalil E, Vakadaris G, et al. Exploring the role of GITR/GITRL signaling: from liver disease to hepatocellular carcinoma. Cancers (Basel). 2024; 16:2609.

[26] Bulliard Y, Jolicoeur R, Windman M, et al. Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med. 2013; 210: 1685-1693.

[27] Mahne AE, Mauze S, Joyce-Shaikh B, et al. Dual roles for regulatory T-cell depletion and costimulatory signaling in agonistic GITR targeting for tumor immunotherapy. Cancer Res. 2017; 77: 1108-1118.

[28] Heinhuis KM, Carlino M, Joerger M, et al. Safety, tolerability, and potential clinical activity of a glucocorticoid-induced TNF receptor-related protein agonist alone or in combination with nivolumab for patients with advanced solid tumors: a phase 1/2a dose-escalation and cohort-expansion clinical trial. JAMA Oncol. 2020; 6: 100-107.

[29] Cascalho M, Platt JL. TNFRSF13B diversification fueled by B cell responses to environmental challenges—a hypothesis. Front Immunol. 2021; 12:634544.

[30] He Z, Wang S, Wu J, Xie Y, Li B. Lower expression of TWEAK is associated with poor survival and dysregulate TIICs in lung adenocarcinoma. Dis Markers. 2022; 2022:8661423.

[31] Sato A, Nagai H, Suzuki A, et al. Generation and characterization of OX40-ligand fusion protein that agonizes OX40 on T-lymphocytes. Front Immunol. 2024; 15:1473815.

[32] Lu X. OX40 and OX40L interaction in cancer. Curr Med Chem. 2021; 28: 5659-5673.

[33] Gao Y, Zhao J, Huang Z, et al. In situ reprogramming of tumors for activating the OX40/OX40 ligand checkpoint pathway and boosting antitumor immunity. ACS Biomater Sci Eng. 2023; 9: 4108-4116.

[34] Porciuncula A, Morgado M, Gupta R, et al. Spatial mapping and immunomodulatory role of the OX40/OX40L pathway in human non-small cell lung cancer. Clin Cancer Res. 2021; 27: 6174-6183.

[35] Zhang X, Yang J, Li F, et al. A CD40-OX40 co-stimulatory circuit orchestrates protective CD4(+) T cell immunity in tuberculosis. Mol Ther. 2026.

[36] Thapa B, Kato S, Nishizaki D, et al. OX40/OX40 ligand and its role in precision immune oncology. Cancer Metastasis Rev. 2024; 43: 1001-1013.

[37] Guo R, Wang Y, Sun J, Li Y, Bie Z, Li X. Microwave ablation triggers OX40L-mediated disruption of TNFRSF4+ Treg immunosuppressive activity. Front Immunol. 2025; 16:1637317.

[38] Fu Y, Lin Q, Zhang Z, Zhang L. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity. Acta Pharm Sin B. 2020; 10: 414-433.

[39] Jiang B, Zhang T, Deng M, et al. BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models. Front Med. 2023; 17: 1170-1185.

[40] Zhang J, Zhou L, Sun X, et al. SHR-1806, a robust OX40 agonist to promote T cell-mediated antitumor immunity. Cancer Biol Ther. 2024; 25:2426305.

[41] Lin L, Hu Y, Guo Z, et al. Gene-guided OX40L anchoring to tumor cells for synergetic tumor “self-killing” immunotherapy. Bioact Mater. 2023; 25: 689-700.

[42] Chen P, Wang H, Zhao L, et al. Immune checkpoints OX40 and OX40L in small-cell lung cancer: predict prognosis and modulate immune microenvironment. Front Oncol. 2021; 11:713853.

[43] Irla M. RANK signaling in the differentiation and regeneration of thymic epithelial cells. Front Immunol. 2020; 11:623265.

[44] Rojas-Rivera D, Beltran S, Munoz-Carvajal F, et al. The autophagy protein RUBCNL/PACER represses RIPK1 kinase-dependent apoptosis and necroptosis. Autophagy. 2024; 20: 2444-2459.

[45] Dhusia K, Su Z, Wu Y. Computational analyses of the interactome between TNF and TNFR superfamilies. Comput Biol Chem. 2023; 103:107823.

[46] Wang H, Wu J, Fang Y, Li Q. MD simulation reveals a trimerization-enhanced interaction of CD137L with CD137. Int J Mol Sci. 2025; 26:1903.

[47] Zhao M, Fu L, Chai Y, et al. Atypical TNF-TNFR superfamily binding interface in the GITR-GITRL complex for T cell activation. Cell Rep. 2021; 36:109734.

[48] Siegmund D, Wagner J, Wajant H. TNF receptor associated factor 2 (TRAF2) signaling in cancer. Cancers (Basel). 2022; 14:4055.

[49] Su Z, Wu Y. A systematic test of receptor binding kinetics for ligands in tumor necrosis factor superfamily by computational simulations. Int J Mol Sci. 2020; 21:1778.

[50] Takayama-Isagawa Y, Komura D, Isagawa T, et al. A transcriptomic analysis of cancer-stromal interactome in lung cancer xenograft models. Cancer Sci. 2025.

[51] Kucka K, Medler J, Wajant H. Analysis of ligand-receptor interactions using bioluminescent TNF superfamily (TNFSF) ligand fusion proteins. Methods Mol Biol. 2021; 2248: 185-200.

[52] Muller D. Targeting co-stimulatory receptors of the TNF superfamily for cancer immunotherapy. BioDrugs. 2023; 37: 21-33.

[53] McVey JC, Beatty GL. Facts and hopes of CD40 agonists in cancer immunotherapy. Clin Cancer Res. 2025; 31: 2079-2087.

[54] Mohamed AH, Obeid RA, Fadhil AA, et al. BTLA and HVEM: emerging players in the tumor microenvironment and cancer progression. Cytokine. 2023; 172:156412.

[55] Segal NH, Logan TF, Hodi FS, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 2017; 23: 1929-1936.

[56] Hong DS, Gopal AK, Shoushtari AN, et al. Utomilumab in patients with immune checkpoint inhibitor-refractory melanoma and non-small-cell lung cancer. Front Immunol. 2022; 13:897991.

[57] Muik A, Garralda E, Altintas I, et al. Preclinical characterization and phase I trial results of a bispecific antibody targeting PD-L1 and 4-1BB (GEN1046) in patients with advanced refractory solid tumors. Cancer Discov. 2022; 12: 1248-1265.

[58] Trub M, Uhlenbrock F, Claus C, et al. Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer. J Immunother Cancer. 2020; 8:e000238.

[59] Compte M, Harwood SL, Munoz IG, et al. A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity. Nat Commun. 2018; 9:4809.

[60] von Karstedt S, Walczak H. An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer. Cell Death Discov. 2020; 6: 14.

[61] Dong Q, Zhang S, Zhang H, et al. MARCO is a potential prognostic and immunotherapy biomarker. Int Immunopharmacol. 2023; 116:109783.

[62] Compte M, Harwood SL, Erce-Llamazares A, et al. An Fc-free EGFR-specific 4-1BB-agonistic trimerbody displays broad antitumor activity in humanized murine cancer models without toxicity. Clin Cancer Res. 2021; 27: 3167-3177.

[63] Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For Immunopathol Dis Therap. 2015; 6: 7-17.

[64] Garris CS, Arlauckas SP, Kohler RH, et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-gamma and IL-12. Immunity. 2018; 49: 1148-1161.e1147.

[65] Yonezawa A, Dutt S, Chester C, Kim J, Kohrt HE. Boosting cancer immunotherapy with anti-CD137 antibody therapy. Clin Cancer Res. 2015; 21: 3113-3120.

[66] Warmuth S, Gunde T, Snell D, et al. Engineering of a trispecific tumor-targeted immunotherapy incorporating 4-1BB co-stimulation and PD-L1 blockade. Onco Targets Ther. 2021; 10:2004661.

[67] Van Den Eeckhout B, Huyghe L, Van Lint S, et al. Selective IL-1 activity on CD8(+) T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication. J Immunother Cancer. 2021; 9:e003293.

[68] Zhou K, Li S, Zhao Y, Cheng K. Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer. Front Immunol. 2023; 14:1127071.

[69] Fountzilas E, Kurzrock R, Vo HH, Tsimberidou AM. Wedding of molecular alterations and immune checkpoint blockade: genomics as a matchmaker. J Natl Cancer Inst. 2021; 113: 1634-1647.

[70] Zhao R, Shu Y, Xu W, et al. The efficacy of immunotherapy in non-small cell lung cancer with KRAS mutation: a systematic review and meta-analysis. Cancer Cell Int. 2024; 24: 361.

[71] Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018; 8: 822-835.

[72] Wang H, Niu X, Jin Z, et al. Immunotherapy resistance in non-small cell lung cancer: from mechanisms to therapeutic opportunities. J Exp Clin Cancer Res. 2025; 44: 250.

[73] Li J, Jiang W, Wei J, et al. Patient specific circulating tumor DNA fingerprints to monitor treatment response across multiple tumors. J Transl Med. 2020; 18: 293.

[74] Wang Y, Peng L, Zhao M, et al. Comprehensive analysis of T cell receptor repertoire in patients with KRAS mutant non-small cell lung cancer. Transl Lung Cancer Res. 2022; 11: 1936-1950.

[75] Mascarelli DE, Rosa RSM, Toscaro JM, et al. Boosting antitumor response by costimulatory strategies driven to 4-1BB and OX40 T-cell receptors. Front Cell Dev Biol. 2021; 9:692982.

[76] Wang YT, Ji WD, Jiao HM, Lu A, Chen KF, Liu QB. Targeting 4-1BB for tumor immunotherapy from bench to bedside. Front Immunol. 2022; 13:975926.

[77] Ujiie N, Kosaka A, Yasuda S, et al. Synergistic activation of STING and CD40 in the tumor microenvironment enhances CD8(+) T-cell-dependent antitumor immunity. Biochem Biophys Res Commun. 2025; 792:152995.

[78] Liu L, Yang L, Li H, Shang T, Liu L. The tumor microenvironment in lung cancer: heterogeneity, therapeutic resistance and emerging treatment strategies (review). Int J Oncol. 2026; 68:11.

[79] Sadeghirad H, Liu N, Monkman J, et al. Compartmentalized spatial profiling of the tumor microenvironment in head and neck squamous cell carcinoma identifies immune checkpoint molecules and tumor necrosis factor receptor superfamily members as biomarkers of response to immunotherapy. Front Immunol. 2023; 14:1135489.

[80] Pimentel JM, Zhou JY, Wu GS. The role of TRAIL in apoptosis and immunosurveillance in cancer. Cancers (Basel). 2023; 15:2752.

[81] Aschmoneit N, Kocher K, Siegemund M, et al. Fc-based Duokines: dual-acting costimulatory molecules comprising TNFSF ligands in the single-chain format fused to a heterodimerizing Fc (scDk-Fc). Onco Targets Ther. 2022; 11:2028961.

[82] Dadas O, Ertay A, Cragg MS. Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives. Front Immunol. 2023; 14:1147467.

[83] Yao Y, Chen C, Li B, Gao W. Targeting HVEM-GPT2 axis: a novel approach to T cell activation and metabolic reprogramming in non-small cell lung cancer therapy. Cancer Immunol Immunother. 2025; 74: 101.

[84] Liu HC, Viswanath DI, Pesaresi F, et al. Potentiating antitumor efficacy through radiation and sustained intratumoral delivery of anti-CD40 and anti-PDL1. Int J Radiat Oncol Biol Phys. 2021; 110: 492-506.

[85] Yan F, Jing C, Duan S, et al. BSA-LDHs-cGAMP in situ sensitization of osteosarcoma: enhancing antitumor efficacy with CD40 agonist antibodies. ACS Biomater Sci Eng. 2025; 11: 4931-4940.

[86] Xu X, Shang B, Wu H, et al. FXR shapes an immunosuppressive microenvironment in PD-L1lo/− non-small cell lung cancer by upregulating HVEM. JCI Insight. 2025; 10:e190716.

[87] Li W, Zhang X, Zhang C, et al. Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy. Nat Commun. 2021; 12:7264.

[88] Yan J, Zhang Y, Du S, et al. Nanomaterials-mediated co-stimulation of toll-like receptors and CD40 for antitumor immunity. Adv Mater. 2022; 34:e2207486.

[89] Qu QX, Zhu XY, Du WW, et al. 4-1BB agonism combined with PD-L1 blockade increases the number of tissue-resident CD8+ T cells and facilitates tumor abrogation. Front Immunol. 2020; 11:577.

[90] Shah P, Forget MA, Frank ML, et al. Combined IL-2, agonistic CD3 and 4-1BB stimulation preserve clonotype hierarchy in propagated non-small cell lung cancer tumor-infiltrating lymphocytes. J Immunother Cancer. 2022; 10:e003082.

[91] Ferencz B, Torok K, Pipek O, et al. Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms. Cancer Immunol Immunother. 2024; 73:114.

[92] Laza-Briviesca R, Cruz-Bermudez A, Nadal E, et al. Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial. Clin Transl Med. 2021; 11:e491.

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2026 The Author(s). Precision Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital.