Abstract
Tumor necrosis factor (TNF) exerts paradoxical effects in cancer, driven by the differential engagement of its two receptors, TNFR1 and TNFR2. While TNFR1 mediates cytotoxic signaling, accumulating evidence indicates that TNFR2 predominantly orchestrates tumor-promoting inflammation and immunosuppression within the tumor microenvironment (TME). TNFR2 is highly expressed on regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and malignant cells, forming a coordinated network that drives immune evasion and contributes to resistance to immune checkpoint blockade (ICB). In this review, we dissect the structural and functional distinctions between transmembrane and soluble TNF and discuss how these differences shape receptor-specific signaling outcomes. We further highlight emerging therapeutic strategies targeting the TNF–TNFR2 axis, including monoclonal antibodies, antibody–drug conjugates (ADCs), and bispecific antibodies, with an emphasis on their ability to selectively remodel the immunosuppressive TME. Finally, we discuss key challenges for clinical translation, including on-target toxicity, patient stratification, and context-dependent TNFR2 biology, and outline future directions such as biomarker-guided therapy and tumor-restricted targeting approaches. Together, these advances position TNFR2 as a promising therapeutic node for overcoming resistance to current immunotherapies.
1 Introduction
TNF is a central inflammatory cytokine that plays multifaceted and context-dependent roles in cancer. Originally identified for its tumoricidal activity, TNF is now recognized as a critical regulator of tumor-promoting inflammation, immune suppression, and therapeutic resistance (, ). In the TME, sustained TNF signaling contributes to cancer progression by shaping immune cell composition, promoting angiogenesis, and fostering chronic inflammation (, ).
Importantly, accumulating evidence suggests that TNF signaling is intimately involved in limiting the efficacy of modern cancer immunotherapies, particularly antibody-based immune checkpoint blockade (, ). Studies have revealed that TNF can paradoxically undermine antitumor immune responses by reinforcing immune tolerance (). For instance, macrophage-derived TNF has been shown to induce resistance to anti-PD-1 therapy by promoting the apoptosis of CD8+ T cells and stabilizing PD-L1 expression on tumor cells, highlighting the need for therapeutic strategies that can selectively modulate TNF signaling without broadly suppressing antitumor immunity (, 7, 8).
The biological complexity of TNF signaling is largely determined by its engagement of two structurally and functionally distinct receptors, TNFR1 and TNFR2. While TNFR1 is ubiquitously expressed and contains an intracellular death domain (DD) that mediates pro-apoptotic and necroptotic signaling pathways, TNFR2 lacks a DD (9). Instead, TNFR2 exhibits a more restricted expression pattern and predominantly activates cell survival and proliferation pathways via NF-κB and PI3K-Akt (10). This receptor-specific signaling dichotomy provides a mechanistic framework for understanding how TNF can simultaneously exert cytotoxic antitumor effects (via TNFR1) and promote tumor survival and immune suppression (via TNFR2). Given the increasing clinical reliance on antibody-based cancer immunotherapies, there is growing interest in exploiting this receptor-selective approach. Rather than globally neutralizing TNF, which may lead to systemic toxicity and dampen baseline antitumor immunity, targeting the TNF–TNFR2 axis offers the potential to selectively dismantle immunosuppressive networks within the TME (11).
While several excellent reviews published in recent years have comprehensively summarized the fundamental biology of TNFR2 and its canonical role in Treg-mediated immunosuppression, this review is specifically designed to bridge the gap between receptor kinetics, emerging TME networks, and therapeutic engineering. Here, we distinctly focus on how the structural kinetics of tmTNF versus sTNF dictate rational drug design. Furthermore, we expand the conventional scope to highlight the critical, self-amplifying roles of CAFs and tumor-intrinsic TNFR2 signaling. Most importantly, we provide a critical evaluation of next-generation, multi-modal targeting strategies—specifically detailing the structural and translational considerations of bispecific antibodies, ADCs, and localized delivery vehicles like engineered oncolytic adenoviruses. By synthesizing these advances, this review offers a definitive roadmap for overcoming the limitations of early-stage monoclonal therapies and advancing TNFR2-targeted interventions toward clinical reality.
2 Genetics, structure, and kinetics of TNF/TNFR interactions
To effectively target the TNF signaling axis, it is crucial to understand the genetic and molecular distinctions between TNF ligands and their receptors. The gene encoding TNF is located within the major histocompatibility complex (MHC) class III region on chromosome 6 (12). TNF is initially synthesized as a 26 kDa transmembrane precursor protein (tmTNF) (13). This membrane-bound form can be proteolytically cleaved by TNF-alpha converting enzyme (TACE/ADAM17) to release a 17 kDa soluble TNF (sTNF) molecule (14). Both tmTNF and sTNF assemble into non-covalent homotrimers to exert their biological functions, but they interact with TNFR1 and TNFR2 differently (Figure 1) (15).
Figure 1
TNFR1 is ubiquitously expressed across nearly all cell types and can be fully activated by both sTNF and tmTNF. Upon binding, the intracellular DD of TNFR1 recruits adapter proteins such as TRADD and FADD, which can subsequently trigger caspase-8-mediated apoptosis or RIPK1/3-mediated necroptosis, underlying the classic cytotoxic effects of TNF (16–18).
In contrast, TNFR2 expression is highly regulated and primarily restricted to immune cells, endothelial cells, and certain tumor cells (19). Crucially, while sTNF can bind to TNFR2, it is generally insufficient to fully activate the receptor. Optimal activation of TNFR2 requires the binding of tmTNF, which facilitates robust receptor clustering and the recruitment of TRAF2 (TNF receptor-associated factor 2), initiating potent NF-κB, MAPK, and PI3K–AKT signaling cascades (20). This dependence on tmTNF restricts TNFR2 signaling to cell–cell contact contexts. Consequently, the design of anti-TNFR2 antibodies must carefully account for whether the therapeutic goal is to block tmTNF binding, lock the receptor in an inactive conformation, or deplete TNFR2-expressing cells entirely.
3 TNFR2 as a key regulator of the Immunosuppressive TME: Tregs, MDSCs, CAFs, and tumor cells
Following the recognition of the context-dependent roles of TNF, TNFR2 has attracted immense attention as a key mediator of immunosuppression within the TME (21, 22). Its restricted expression pattern positions TNFR2 as a critical regulator of the immunosuppressive niche (Figure 2). Elevated expression of TNFR2 across multiple cell types in the TME is strongly associated with shortened overall survival (OS) and progression-free survival (PFS) in cancer patients (23, 24).
Figure 2
3.1 Tregs and MDSCs
TNFR2 governs Treg homeostasis, phenotypic stability, and suppressive capacity through the activation of NF-κB and PI3K–AKT pathways (25, 26). Concurrently, TNFR2 signaling in MDSCs promotes the upregulation of immunosuppressive mediators, including arginase-1 (ARG1), IL-10, and TGF-β, facilitating their recruitment and reinforcing tumor immune evasion (27).
3.2 Cancer-associated fibroblasts and tumor cells
Beyond traditional immune suppressors, recent studies highlight that TNFR2 is profoundly expressed on CAFs and various tumor cells (28, 29). CAFs play structural and regulatory roles within the TME. Upon TNFR2 activation, they are stimulated to secrete various extracellular matrix components and immunosuppressive cytokines. Specifically, signaling through the TNFR2–NF-κB–IRF1 axis induces CAFs to release IL-33, thereby driving epithelial-mesenchymal transition (EMT) and enhancing the migration and invasion of gastric cancer cells (23, 30). Furthermore, many malignant cells directly upregulate TNFR2 to co-opt its NF-κB-driven survival signals, promoting aggressive proliferation and resistance to apoptosis (29, 30). The intense crosstalk among TNFR2+ tumor cells, CAFs, Tregs, and MDSCs forms a robust, self-amplifying immunosuppressive network that may contribute to the attenuation of anti-tumor immune responses.
4 Next-generation TNFR2-targeting strategies: monoclonal antibodies, ADCs, and bispecifics
Unlike global TNF blockade, which risks systemic infection and abolishes TNFR1-mediated tumor cell death, targeting TNFR2 selectively dismantles the TME’s defensive shield (11, 31). While early clinical evaluations focused on monoclonal antibodies (Table 1), the field is rapidly advancing toward more sophisticated multi-modal formats designed to enhance efficacy and overcome specific limitations (32). To highlight the rapid evolution of these multimodal and cell-type specific approaches, we have summarized the most promising strategies currently in preclinical development (Table 2), which aim to overcome the limitations of conventional monoclonal therapies through enhanced spatial and cellular precision.
Table 1
| Drug name | Developer | Antibody isotype/format | Clinical stage | Specific tumor indications |
|---|---|---|---|---|
| BI-1808 | BioInvent | Human IgG1 (Ligand-blocking, Fc-enabled for ADCC) | Phase I/II | Advanced solid tumors, Cutaneous T-cell lymphoma (CTCL) |
| BI-1910 | BioInvent | Human IgG1 (Non-ligand blocking) | Phase I/II | Advanced solid tumors (e.g., HCC, NSCLC) |
| LBL-019 | Leads Biolabs | Humanized Monoclonal Antibody | Phase I/II | Advanced solid tumors, Refractory malignancies |
| HFB200301 | HiFiBiO | Fully Human IgG1 (Enhanced cross-linking) | Phase I | Advanced solid tumors (e.g., Melanoma, NSCLC) |
| SIM-235 | Simcere | Humanized IgG1 | Phase I | Advanced solid tumors |
| NBL-020 | NovaRock/CSPC | Fully Human Monoclonal Antibody | Phase I | Advanced solid tumors (often explored combo with PD-1) |
| AN3025 | Adlai Nortye | Humanized Monoclonal Antibody | Phase I | Advanced solid tumors |
| BITR2101 | Boston Immune (BITT) | Monoclonal Antibody | Phase I | Relapsed/Refractory CTCL, Non-Hodgkin Lymphoma |
Clinical-stage of anti-TNFR2 antibodies in oncology.
Table 2
| Therapeutic modality | Representative format/targets | Key mechanism for cell-type specificity | Ref. |
|---|---|---|---|
| Bispecific Antibodies(Adaptive Checkpoint) | TNFR2 × PD-L1 | TME Co-localization: Anchors TNFR2 blockade strictly at PD-L1-rich tumor sites to rescue exhausted CD8+ T cells without systemic toxicity. | (40) |
| Bispecific Antibodies(Innate Checkpoint) | TNFR2 × CD47 | Avidity-driven Dual Blockade: Selectively binds dual-positive cells to dismantle TAM phagocytosis barriers and reverse adaptive immunosuppression. | (39) |
| Antibody-Drug Conjugates(ADCs) | Dual-targeting BsADCs (e.g., TNFR2 ×CCR8) | Payload Precision: Requires dual-antigen engagement to internalize and deliver cytotoxins strictly to highly immunosuppressive TME subsets. | (38) |
| Localized Delivery Vehicles | Armed Oncolytic Viruses (e.g., engineered AdV) | Spatial Confinement: Drives localized TNFR2 modulation and microenvironment remodeling exclusively within the viral-infected TME. | (39) |
Emerging preclinical modalities and cell-type specific TNFR2-targeting strategies.
4.1 Monoclonal antibodies
Monoclonal anti-TNFR2 antibodies operate through dual mechanisms: directly antagonizing tmTNF-TNFR2 signaling to reverse Treg/MDSC suppressive functions, and utilizing Fc-dependent effector functions (such as ADCC and ADCP) to physically deplete TNFR2-high immunosuppressive cells (26, 33). The mechanistic foundation for these therapeutic approaches stems from seminal studies that unraveled the highly pleiotropic nature of TNFR2 within the TME. Early work by Torrey et al. established that antagonistic TNFR2 antibodies could simultaneously inhibit highly immunosuppressive Tregs and directly induce cell death in TNFR2-expressing tumor cells, primarily by blocking ligand binding and depriving them of essential NF-κB-driven survival signals (34). Adding a critical layer to this paradigm, Tam et al. demonstrated that dominant agonist antibodies targeting TNFR2 can provide potent Fc-dependent costimulation; this process relies on FcγR-mediated cross-linking to directly activate CD8+ T cells and promote robust, durable antitumor immunity (35). These dichotomous mechanisms—simultaneous Treg suppression and Fc-driven CD8+ T cell activation—collectively underscore why precise antibody engineering is absolutely essential to selectively harness TNFR2 biology without broadly disrupting immune homeostasis.
4.2 Antibody-drug conjugates and localized delivery vehicles
To leverage the dense overexpression of TNFR2 on Tregs and specific tumor cells, TNFR2-targeted ADCs are emerging as a promising strategy. By attaching a potent cytotoxic payload to an anti-TNFR2 antibody, ADCs can selectively deliver lethal doses of chemotherapy directly into the immunosuppressive TME. However, the applicability of ADCs faces distinct constraints: the payload must be carefully selected to avoid profound systemic immune depletion (on-target, off-tumor toxicity), as baseline TNFR2 expression is required for normal immune homeostasis and tissue repair (36). To mitigate these on-target, off-tumor toxicities, next-generation ADC designs are increasingly incorporating dual-targeting strategies. By engineering bispecific ADCs that pair a TNFR2-directed component with a specific “targeting arm” against a well-defined tumor-associated antigen (TAA), the cytotoxic payload can be selectively routed to malignant cells. This strict requirement for dual-antigen engagement ensures that cell death is restricted to the TME, sparing peripheral TNFR2+ immune populations. To circumvent these systemic constraints, recent strategies have utilized engineered oncolytic adenoviruses to confine TNF/TNFR2 blockade strictly within the TME, yielding potent local anti-tumor efficacy while mitigating the risks of systemic receptor suppression (37).
4.3 Bispecific antibodies
Bispecific antibodies represent another frontier, physically bridging TNFR2 blockade with other immunomodulatory pathways. Formats co-targeting TNFR2 and adaptive immune checkpoints (e.g., PD-1/PD-L1, CTLA-4), innate checkpoints (e.g., CD47), or Treg-associated targets (e.g., CCR8) are designed to simultaneously release immune brakes, profoundly deplete immunosuppressive populations, and aggressively drive localized T-cell activation (38–40). A critical engineering advantage of these bispecific formats is their capacity to achieve cell-type specificity through avidity-driven targeting. By strategically tuning the binding kinetics—pairing a high-affinity targeting arm against a TME-enriched checkpoint (e.g., CD47 heavily expressed on tumor-associated macrophages and malignant cells) with a functionally attenuated, lower-affinity TNFR2 arm—the therapeutic molecule selectively anchors only to cells co-expressing both targets. This mechanism prevents the systemic engagement of solitary TNFR2 on circulating leukocytes. Consequently, profound TNFR2 modulation, such as the depletion of Tregs or the targeted costimulation of terminally exhausted CD8+ T cells, is anatomically confined to the tumor site. For instance, novel PD-L1/TNFR2 bispecific antibodies have been shown to significantly increase tumor-specific targeting over monotherapies, comprehensively remodeling the TME by depleting Tregs and monocytic MDSCs (M-MDSCs) while rescuing CD8+ T cell exhaustion (40). Similarly, dual blockade formats targeting both TNFR2 and CD47 have demonstrated remarkable synergistic efficacy in dismantling both innate phagocytosis barriers and adaptive immunosuppression (39). The primary constraints hindering their rapid utilization include the complex engineering required to balance the binding affinities of the two arms, preventing steric hindrance, and managing the risk of hyper-inflammatory cytokine release syndrome (CRS) (41).
5 Challenges and future perspectives
While preclinical and early clinical data for TNFR2-targeted therapies are highly encouraging, successful translation hinges on managing the receptor’s pleiotropic biology. The fundamental hurdle remains achieving true tumor-specificity. Given that TNFR2 is essential for maintaining peripheral immune homeostasis, systemically depleting TNFR2-expressing cells with potent ADCs or enhanced-ADCC antibodies carries a severe risk of autoimmune-like toxicities. Navigating this narrow therapeutic window requires a profound shift in how these agents are engineered and delivered.
Moving forward, clinical success will rely heavily on robust patient stratification—specifically pinpointing those with immunologically “cold” tumors driven by dense networks of TNFR2+ CAFs and Tregs. Furthermore, rather than relying on simple receptor blockade, the field must aggressively exploit the distinct signaling kinetics of tmTNF versus sTNF. Ultimately, next-generation platforms like conditionally active biologics and rationally designed bispecifics are uniquely positioned to provide the spatial precision required to safely dismantle immunosuppression and conquer ICB resistance.
Statements
Author contributions
XK: Conceptualization, Writing – original draft, Writing – review & editing. XT: Writing – review & editing. SW: Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Foundation of Science Technology Department of Zhejiang Province (LKLZ26H080001), Key R&D Program of Hangzhou Science and Technology Bureau (2025SZD1B13), National Natural Science Foundation of China (82470182), Construction Fund of Key Medical Disciplines of Hangzhou-Laboratory Diagnostics (2025HZZD01), Natural Science Foundation of Hangzhou (2024SZRYBC080002).
Acknowledgments
The authors are grateful to Xiaoli Kang and Hui Wu for their help with figure design and graphical illustration. Additionally, the figures were created by Figdraw.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
antibody, immune resistance, immunotherapy, TNF, TNFR2
Citation
Kang X, Tong X and Wang S (2026) Antibody targeting of the TNF–TNFR2 axis to overcome tumor immune resistance. Front. Immunol. 17:1809305. doi: 10.3389/fimmu.2026.1809305
Received
11 February 2026
Revised
30 April 2026
Accepted
30 April 2026
Published
14 May 2026
Volume
17 - 2026
Edited by
Yuanzhi Chen, Xiamen University, China
Reviewed by
Leslie Greene, aTyr Pharma, United States
Updates
Copyright
© 2026 Kang, Tong and Wang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xiaozhen Kang, kxz1514@163.com; Shibing Wang, wangshibing@hmc.edu.cn; Xiangmin Tong, tongxiangmin@163.com
†Present address: Xiaozhen Kang, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, United States
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.