This article systematically summarizes the molecular functions of CD28 and its central role in cancer immunotherapy, revealing the importance of CD28 signaling in CAR-T cell and TIL therapies, and exploring the clinical potential of CD28-targeting bispecific antibodies, providing theoretical and experimental support for next-generation immunotherapeutic strategies.
Literature Overview
This article, titled 'CD28 co-stimulation: novel insights and applications in cancer immunotherapy', was published in 'Nature Reviews Immunology'. It reviews and summarizes recent research on T cell signaling mechanisms, particularly the role of CD28 as a co-stimulatory receptor in cancer immunotherapy. The researchers analyzed the molecular structure, signaling pathways, and functional roles of CD28 in regulating T cell metabolism, epigenetic modification, and RNA processing, while also discussing the mechanisms of CD28 downregulation within the tumor microenvironment and its interactions with immune checkpoint receptors such as PD-1 and CTLA-4. The study revisits the failure and resurgence of CD28-targeting therapeutic approaches, and how novel bispecific antibodies and cell engineering technologies can circumvent cytokine release syndrome and enhance anti-tumor efficacy. Finally, it discusses the role of CD28 in tumor immune escape and how modulating CD28 signaling can improve the persistence and function of CAR-T and TIL therapies.
Background Knowledge
CD28 is a critical co-stimulatory receptor in T cell activation and plays a central role in anti-tumor immune responses. Despite the clinical trial failure of the CD28 superagonist TGN1412 due to severe side effects, recent advances in antibody engineering and cell therapy have re-established CD28 as an important target in cancer immunotherapy. The binding of CD28 to its ligands CD80/CD86 promotes T cell proliferation, survival, and cytokine secretion, but this process is often suppressed in the tumor microenvironment, leading to T cell exhaustion. Moreover, CD28 signaling is closely linked with regulatory mechanisms such as E3 ubiquitin ligases, microRNAs, and RNA splicing factors, influencing metabolic reprogramming, epigenetic modifications, and functional persistence of T cells. Currently, several bispecific antibodies and chimeric antigen receptor (CAR) T cell therapies targeting CD28 have entered clinical trials, showing potential when combined with immune checkpoint blockade (e.g., anti-PD-1). These advancements provide new molecular targets and clinical pathways for developing safer and more effective cancer immunotherapies.
Research Methods and Experiments
This study employs structure-function analysis, protein interaction studies, and gene editing technologies to dissect the molecular architecture of CD28, including the functional roles of its extracellular domain, transmembrane domain, and intracellular signaling motifs (such as PYAP, YMNM, and PRRP). Furthermore, the research team evaluated the role of CD28 co-stimulation in T cell expansion, persistence, and anti-tumor function using CAR-T and TIL models. By developing bispecific and multispecific antibodies, the researchers mimicked the immunological synapse between T cells and tumor cells to analyze the impact of CD28 signaling on T cell activation. The study also explored the cross-regulation between CD28 and co-inhibitory receptors such as CTLA-4 and PD-1, and combined animal models to assess the efficacy of CD28-targeted therapies in different tumor microenvironments.
Key Conclusions and Perspectives
Research Significance and Prospects
CD28 plays a central regulatory role in cancer immunotherapy, particularly in T cell persistence, metabolic reprogramming, and epigenetic modifications. Future studies may further explore the synergistic mechanisms between CD28 and different co-stimulatory or co-inhibitory molecules, optimize bispecific antibody design for improved targeting and safety, and enhance T cell function by modulating RNA-binding proteins and splicing factors. Additionally, developing small molecules or antibody drugs that stabilize CD28 signaling may improve immunotherapy responses in 'cold tumors'. CD28-targeted therapy could become a pivotal node in the development of next-generation cell therapies and antibody drugs, providing theoretical support for personalized immunotherapy.
Conclusion
This article systematically summarizes the molecular mechanisms and clinical applications of the CD28 co-stimulatory receptor in cancer immunotherapy, revealing its multifaceted roles in T cell functional maintenance, metabolic regulation, epigenetic modification, and RNA splicing. The study highlights that the strength and duration of CD28 signaling influence the phenotype and persistence of CAR-T cell therapy, while bispecific antibody strategies can effectively enhance anti-tumor T cell activity and reduce the risk of cytokine release syndrome. In the tumor microenvironment, CD28 downregulation correlates with T cell exhaustion, and restoring its function may improve immunotherapy responses. Furthermore, interactions between CD28 and E3 ubiquitin ligases, microRNAs, and RNA-binding proteins provide new molecular targets and regulatory pathways for cancer therapy. These research advancements lay a solid theoretical foundation for next-generation immunotherapy strategies (e.g., multispecific antibodies, gene-edited T cells), and open new directions for clinical translation and personalized treatment design.
