T Cell and B Cell Co-Stimulation Mechanisms in Cancer Immunotherapy

Effective cancer immunotherapy relies not only on antigen recognition by T and B lymphocytes but also on co-stimulatory signals that reinforce activation, expansion and memory formation. T cells require two signals: engagement of the T cell receptor with peptide–major histocompatibility complex and a secondary input from co-stimulatory receptors such as CD28, CD27 or members of the tumour necrosis factor receptor superfamily. B cells also contribute to anti-tumour responses by presenting antigen and delivering reciprocal co-stimulation via ligands such as CD70. The interplay between these signals shapes the immunological synapse, influences cytokine secretion patterns and determines the durability of effector and memory responses. Harnessing co-stimulation has underpinned the design of novel agents—from agonistic antibodies to bispecific molecules—and guided combination regimens with checkpoint inhibitors to bolster tumour clearance while limiting immune-related toxicity.

Research from Nature Portfolio

A comprehensive analysis of immune checkpoint and co-stimulatory gene expression across diverse cancer cell lines has revealed that certain co-stimulatory receptors may paradoxically act as tumour suppressors in specific contexts. By defining a signature of six genes—including CD27—with low expression in many cell lines, investigators demonstrated an inverse correlation between this metagene signature and several oncogenic pathways. Tumours exhibiting higher expression of these co-stimulatory molecules showed improved patient survival and reduced activation of transforming growth factor-β, angiogenesis and epithelial–mesenchymal transition programmes. This work highlights a complex role for co-stimulatory receptors in tumour cell biology and suggests that therapeutic strategies aiming to restore or enhance their expression might augment the efficacy of immune checkpoint blockade.

T Cell and B Cell Co-Stimulation Mechanisms in Cancer Immunotherapy publication trend

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

Technical terms

Co-stimulatory receptor: A surface molecule on lymphocytes that delivers a secondary activation signal upon binding its ligand, essential for full immune activation.

Immunological synapse: The specialised interface between a lymphocyte and an antigen-presenting cell that organises receptors, signalling molecules and adhesion proteins to facilitate communication.

Tumour necrosis factor receptor superfamily (TNFRSF): A group of receptors that regulate immune cell survival, proliferation and differentiation through binding to TNF-related ligands.

Bispecific antibody: An engineered immunoglobulin capable of simultaneously binding two distinct antigens or receptors, enabling coordinated therapeutic functions.

References

1. CD70 recruitment to the immunological synapse is dependent on CD20 in B cells. Proceedings of the National Academy of Sciences of the United States of America (2025).
2. Tumor intrinsic immunity related proteins may be novel tumor suppressors in some types of cancer. Scientific Reports (2019).
3. Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives. Frontiers in Immunology (2023).
4. Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy. Cancer Immunology, Immunotherapy (2020).