T Cell Checkpoint Modulation in Immunotherapy

T cell checkpoint modulation harnesses or inhibits natural regulatory pathways that control T cell activation, proliferation and survival. Central to this approach are inhibitory receptors such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which upon ligation attenuate antigen receptor signalling to maintain self-tolerance and prevent immunopathology. In cancer, malignant cells exploit these checkpoints to evade immune surveillance. Therapeutic blockade of PD-1/PD-L1 and CTLA-4 has transformed treatment of multiple tumour types by releasing T cells from inhibition, thereby restoring cytotoxic function. Progress in this field extends beyond monoclonal antibodies to include small-molecule inhibitors, bispecific agonists, combination regimens and an increasing appreciation of checkpoint crosstalk in diverse cellular compartments. These strategies hold promise for enhancing efficacy, overcoming resistance and broadening applications to haematological malignancies, chronic infections and autoimmune disorders.

Research from Nature Portfolio

Recent studies reveal that immunocyte-derived small extracellular vesicles bearing PD-1 and CD80 induce adaptive remodelling of tumour cell PD-L1 distribution, reduce membrane PD-L1 and increase vesicular secretion, ultimately converting tumours to an immunologically cold phenotype. Analysis of vesicle-bound checkpoints provides a novel biomarker signature to distinguish responders from non-responders to PD-1 blockade. In parallel, targeting SHP-2 signalling in myeloid lineages has uncovered a crucial role for PD-1–SHP-2 in restraining myeloid differentiation and antitumour immunity. Conditional deletion of SHP-2 or PD-1 in myeloid cells augments GM-CSF-driven transcriptional programmes, enhances macrophage and dendritic cell activation and limits tumour growth, highlighting myeloid PD-1 as a therapeutic target distinct from T cell checkpoints.

T Cell Checkpoint Modulation in Immunotherapy publication trend

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

Technical terms

Immune checkpoint: Regulatory pathways that temper T cell activity to prevent excessive immune responses.

PD-1 (programmed cell death protein 1): An inhibitory receptor on T cells that dampens activation upon ligand binding.

CTLA-4 (cytotoxic T-lymphocyte-associated protein 4): A coinhibitory receptor that competes with CD28 to limit T cell costimulation.

SHP-2 (Src homology region 2 domain-containing phosphatase 2): A protein tyrosine phosphatase recruited by phosphorylated checkpoints to dephosphorylate signalling proteins.

Small extracellular vesicles (sEVs): Membranous particles released by cells that can carry checkpoint proteins and modulate immune interactions.

T cell receptor (TCR): The antigen-specific receptor on T cells that initiates activation upon peptide–MHC engagement.

References

1. PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression. Nature Communications (2024).
2. SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses. Nature Immunology (2022).
3. PD-1 signaling negatively regulates the common cytokine receptor γ chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity. Cell Research (2023).
4. PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Activation. Frontiers in Immunology (2019).
5. Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD-1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy. Cell Reports (2019).