Nature Reviews Immunology | CD28 Co-stimulation: Novel Insights and Applications in Cancer Immunotherapy

This review comprehensively summarizes the critical roles of CD28 in T cell signaling, metabolic regulation, mRNA processing, and epigenetic control, and introduces recent advances in cancer immunotherapy involving CD28 agonists, bispecific antibodies, and multispecific antibodies.

 

Literature Overview
This article, entitled 'CD28 co-stimulation: novel insights and applications in cancer immunotherapy', published in the journal Nature Reviews Immunology, reviews and summarizes the central role of CD28 in T cell co-stimulation and its recent applications in cancer immunotherapy. The study explores the molecular mechanisms and regulatory networks of CD28 and its clinical potential in immunotherapeutic interventions, highlighting its importance in enhancing T cell function and overcoming immune evasion within the tumor microenvironment.

Background Knowledge
CD28 is a critical co-stimulatory receptor during T cell activation, first identified in the late 1970s through hybridoma technology. Its ligands, CD80 and CD86, are primarily expressed on antigen-presenting cells (APCs) such as dendritic cells and activated B cells. Activation of CD28 enhances T cell proliferation, survival, cytokine secretion, and metabolic reprogramming, making it a pivotal mechanism in immune checkpoint blockade, adoptive cell therapy, and bispecific antibody treatments. However, in 2006, CD28-targeted therapies faced setbacks due to severe side effects caused by cytokine release syndrome (CRS) during the TGN1412 clinical trial. In recent years, with advances in antibody engineering and cell therapy technologies, CD28 agonists have regained attention as promising agents in cancer immunotherapy. CD28 signaling plays a crucial role in T cell metabolism, epigenetic regulation, RNA splicing, and post-translational modifications. Its regulatory mechanisms involve E3 ubiquitin ligases (such as CBL-B and FBW7) and microRNAs (such as miR-17~92 and miR-155). Studies have also revealed that CD28 expression levels are closely linked to T cell exhaustion, with signal strength influencing the persistence and anti-tumor activity of CAR-T and TIL cell therapies. Therefore, CD28 has emerged as a key target for various next-generation immunotherapeutic strategies, including bispecific antibodies, multispecific antibodies, chimeric co-stimulatory receptors, and switch receptors.

 

 

Research Methods and Experiments
This review summarizes the structural and functional relationships of CD28, including cis-signaling, interactions with ubiquitin ligases, metabolic regulation, mRNA processing, microRNA regulation, and epigenetic control. The research team analyzed the molecular basis of CD28 signaling using structural biology, biochemical assays, and functional validation techniques, while employing genomics, proteomics, and metabolomics to investigate its multi-layered regulatory roles in T cell function. Furthermore, the authors discussed the role of CD28 in the tumor microenvironment, particularly its function in maintaining T cell responses and preventing exhaustion.

Key Conclusions and Perspectives

• CD28 is the central co-stimulatory receptor for T cell activation and plays a critical role in immunotherapeutic responses.
• The PYAP motif in CD28 is the dominant signaling domain, whose phosphorylation recruits LCK and PKCθ to activate downstream pathways such as NF-κB, AP1, and mTOR.
• CD28 can sustain T cell functionality in the tumor microenvironment through cis-signaling, and the loss of cis-signaling impairs T cell migration and anti-tumor activity.
• E3 ubiquitin ligases such as CBL-B and FBW7 regulate PD1 expression, thereby indirectly affecting CD28 signaling strength.
• CD28 signaling is closely linked to T cell metabolic regulation, influencing the balance between glycolysis and mitochondrial respiration, which determines T cell differentiation and persistence.
• Combining CD28 agonists with PD1 inhibitors or CAR-T therapies can enhance anti-tumor immune responses and mitigate T cell exhaustion.
• Bispecific antibodies (e.g., TAA × CD28) when combined with CD3 antibodies or immune checkpoint inhibitors, can effectively activate T cells and enhance anti-tumor responses.

Research Significance and Prospects
As a key co-stimulatory receptor for T cell activation, deeper understanding of CD28’s molecular mechanisms can aid in developing more effective cancer immunotherapies. Future combination strategies involving CD28 agonists with CAR-T, T cell redirection therapies, or immune checkpoint inhibitors may represent important approaches for enhancing anti-tumor responses. Moreover, modulating CD28 signal strength or stability may improve the persistence of immune memory and effector functions in T cell therapies.

 

 

Conclusion
CD28 plays an irreplaceable role in T cell co-stimulation and immunotherapy, with its signaling mechanisms influencing T cell metabolism, functional persistence, and anti-tumor activity. Although early CD28 agonists were limited due to cytokine storm events, recent advances in antibody engineering and cell therapy technologies have re-established CD28 as a vital target in cancer immunotherapy. Modulating CD28 signaling can improve T cell metabolic fitness, maintain stem-like phenotypes, and enhance the overall efficacy of immunotherapy. Furthermore, combining CD28 agonists with PD1 inhibitors, CAR-T cell therapy, or bispecific antibodies may offer novel therapeutic opportunities for treating solid tumors. Cyagen Biosciences provides relevant services including gene-edited mouse models, CAR-T cell production, and tumor drug efficacy evaluation to support CD28-related research.

 

Michael T Lotze, Scott H Olejniczak, and Dimitris Skokos. CD28 co-stimulation: novel insights and applications in cancer immunotherapy. Nature Reviews Immunology.