Immune Checkpoint Modulation in Cancer Immunotherapy

The modulation of immune checkpoints represents a paradigm shift in cancer treatment by harnessing the patient’s own immune system to recognise and eliminate malignant cells. Immune checkpoints are regulatory pathways that maintain self-tolerance and limit collateral tissue damage during immune responses. Tumours exploit these inhibitory circuits—most notably the programme-death 1 (PD-1)/programme-death ligand 1 (PD-L1) axis and cytotoxic T-lymphocyte antigen-4 (CTLA-4)—to evade immune surveillance. Therapeutic antibodies targeting PD-1, PD-L1 or CTLA-4 release these brakes on T cells, restoring cytotoxic activity against cancer cells. Clinical success has been most pronounced in melanoma, non-small-cell lung cancer and renal cell carcinoma, yet response rates vary and resistance emerges in a subset of patients. Resistance mechanisms include upregulation of alternate inhibitory receptors, alterations in antigen presentation machinery and modulation of the tumour microenvironment. Current strategies to broaden efficacy and overcome resistance involve combination therapies—pairing checkpoint inhibitors with targeted agents, radiotherapy or cell-based immunotherapies—and novel checkpoint targets such as LAG-3 and TIGIT. Biomarker development, encompassing tumour mutational burden, neoantigen load and immune gene signatures, aims to predict responsiveness and personalise treatment. Together, these advances underscore the global significance of checkpoint modulation as a versatile and transformative approach in oncology.

Research from Nature Portfolio

Integrative molecular and clinical modelling has illuminated predictors of response to PD-1 blockade in metastatic melanoma. By combining whole-exome and transcriptome sequencing with clinical annotations, researchers have shown that features of antigen presentation, including both MHC-I and MHC-II expression profiles, refine the prediction of therapeutic benefit. The study also revealed that prior exposure to CTLA-4 blockade reshapes the tumour immune landscape, necessitating distinct models for ICB-experienced versus ICB-naive patients.

An in vivo analysis of antigen-presenting dendritic cells has clarified the dynamic role of PD-L1 on these cells in modulating T cell activation. Following antigen uptake, conventional type 1 dendritic cells upregulate PD-L1, which both limits cytotoxic T lymphocyte killing of the presenting cell and tempers antitumour responses. Blocking PD-L1 on dendritic cells reinvigorates intratumoural T cell activity and enhances tumour control, emphasising the dual importance of tumour and host cell PD-L1 expression in immune suppression.

Immune Checkpoint Modulation in Cancer Immunotherapy publication trend

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

Technical terms

Immune checkpoint: A molecular pathway that downregulates immune responses to maintain self-tolerance and prevent tissue damage.

PD-1 (Programme-death 1): An inhibitory receptor on activated T cells that, upon binding PD-L1 or PD-L2, reduces T cell proliferation and cytotoxic function.

PD-L1 (Programme-death ligand 1): A ligand expressed on tumour and immune cells that engages PD-1 to inhibit T cell activity.

CTLA-4 (Cytotoxic T-lymphocyte antigen-4): An inhibitory receptor on T cells that competes with the costimulatory receptor CD28, attenuating T cell activation.

Tumour microenvironment: The complex milieu of cancer cells, stromal cells, immune cells and extracellular matrix that influences tumour progression and response to therapy.

Neoantigen: A tumour-specific peptide arising from somatic mutations, capable of being presented by MHC molecules and recognised by T cells.

References

1. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. Nature Medicine (2019).
2. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nature Communications (2020).
3. A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma. Cell (2024).
4. Regulatory mechanisms of PD-1/PD-L1 in cancers. Molecular Cancer (2024).
5. Prior anti-CTLA-4 therapy impacts molecular characteristics associated with anti-PD-1 response in advanced melanoma. Cancer Cell (2023).