T Cell Activation Mechanisms in Cancer Immunotherapy

T cell activation in cancer immunotherapy hinges on the integration of antigen recognition through the T-cell receptor with secondary costimulatory signals that ensure full effector differentiation, proliferation and survival. Following engagement of peptide–MHC complexes on antigen-presenting cells, costimulatory receptors such as CD28 and members of the tumour necrosis factor receptor (TNFR) superfamily, notably 4-1BB (CD137), deliver essential signals via adaptor proteins and ubiquitin-mediated pathways. These signals converge on transcription factors including NF-κB and MAPKs to induce cytokine secretion, cytotoxic granule release and metabolic reprogramming. Checkpoint pathways (PD-1, CTLA-4) counterbalance activation, and their blockade has revolutionised treatment of many malignancies. Recent advances exploit engineered agonists or multi-specific antibodies to potentiate costimulation in the tumour microenvironment while limiting systemic toxicity. Chimeric antigen receptor (CAR) T cells incorporate costimulatory domains such as CD137 into synthetic receptors, enhancing persistence and antitumour efficacy. Together, these approaches illustrate the central role of orchestrated signalling events in mobilising T cells against cancer.

Research from Nature Portfolio

Recent studies have introduced multi-specific nano-antibody platforms that co-target PD-L1, 4-1BB and NKG2A (or TIGIT) on natural killer and CD8+ T cells. These tri-specific constructs engage both innate and adaptive effector cells, enhancing their activation, proliferation and tumour cell cytotoxicity in patient-derived organoids and humanised mouse models. Another investigation described a CD137×PD-L1 bispecific antibody that provides context-dependent costimulation: clustering 4-1BB only in the presence of high PD-L1 levels amplifies T-cell priming and intra-tumour CD8+ T-cell expansion while limiting systemic inflammatory cytokine release and hepatotoxicity.

T Cell Activation Mechanisms in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in t cell activation mechanisms in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

Antigen-presenting cell: A cell that displays processed antigen peptides on major histocompatibility complex molecules for recognition by T cells.

Costimulatory receptor: A receptor on T cells that provides a second signal, alongside T-cell receptor engagement, required for full activation and survival.

4-1BB (CD137): A costimulatory receptor of the TNFR superfamily expressed on activated T cells and natural killer cells, promoting proliferation, survival and effector functions upon ligation.

PD-L1: Programmed death-ligand 1, an immune checkpoint ligand that binds PD-1 on T cells to suppress their activation.

NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells, a family of transcription factors central to immune response and cell survival signalling.

TRAF: TNF receptor–associated factors that act as adaptor proteins recruited to activated TNFR superfamily members to facilitate downstream signalling.

Chimeric antigen receptor (CAR): A synthetic receptor engineered into T cells, combining antigen recognition domains with intracellular signalling modules to direct cytotoxic activity against tumour cells.

Natural killer cell (NK cell): An innate lymphocyte capable of recognising and killing infected or malignant cells without prior antigen sensitisation.

Bispecific antibody: A recombinant antibody engineered to bind two distinct antigens or epitopes simultaneously.

References

1. Orchestrating NK and T cells via tri-specific nano-antibodies for synergistic antitumor immunity. Nature Communications (2024).
2. A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade. Nature Communications (2021).
3. 4-1BB immunotherapy: advances and hurdles. Experimental & Molecular Medicine (2024).
4. CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects. Science Advances (2023).
5. CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs. Frontiers in Immunology (2018).