CD96 (CD96 Molecule)

We have shown how a single point mutation of an amino acid residue located in the centre of the F strand of TIGIT dictates its interaction affinity with its ligand. These findings can provide a framework for the development of small-sized non-antibody therapeutics specifically targeted towards nectin-4 overexpressing cancer cells with minimal off-target effects on healthy cells.

We also engineered epithelial cell adhesion molecule (EpCAM)-targeted human chimeric antigen receptor (CAR)-T cells deficient in CD96 expression, which robustly target PTCs and demonstrate remarkable therapeutic potential against CRC. Overall, our study uncovers CD96 as a previously unrecognized axis of vulnerability within the PTC-driven microenvironment, offering a promising avenue to enhance CRC therapeutic outcomes.

This review comprehensively discusses the mechanistic basis, therapeutic implications, combination strategies, and future directions of immune checkpoints beyond PD-1 and CTLA-4, emphasizing biomarker development, precision medicine approaches, and balancing efficacy with safety.

Notably, CAR-T cells exhibited synergistic antitumor responses when combined with TIGIT blockade, whereas CAR-NKT cells showed greater sensitivity to CD96 blockade in vivo. These findings highlight the divergent therapeutic dynamics of CAR-T and CAR-NKT cells and provide mechanistic insights that inform the rational design of next-generation cell therapies and combinatorial strategies for solid tumors.

ILC1 from NV-HCC also displayed enhanced IL-2/IL-15 signaling and interactions with CD8 + T cells via HLA-E, suggestive of potential antitumor crosstalk. While our single-cell cohort size was limited, necessitating validation in larger datasets, our study reveals etiology-associated differences in ILC phenotypes in HCC and provides insight into their potential roles in modulating immune responses within the tumor microenvironment.

These effects are observed with CAR-T cells targeting CD25 or CD96 as AML-associated targets. Our results indicate that CXCR4 strengthens CAR-T cell memory and durability, offering a strategy to improve immunotherapy outcomes in AML and beyond.

Incorporating these markers in combination with established aberrant markers can enhance the identification of LSCs and help distinguish them from HSCs in both CD34 + and CD34- AML. Our findings support the use of an expanded combinatorial marker panel and warrants its further evaluation in a larger AML cohort, particularly in the context of measurable residual disease (MRD) assessment, prognostication and correlation with treatment response and survival outcomes.

Importantly, CD96-CAR T cells did not inhibit colony formation by HSPCs during manufacturing. These findings indicate that CD96 is a promising target for AML immunotherapy, and the combination of CD96-CAR and CD33-CCR may represent a potent strategy for patients with CD96-positive AML while preserving normal hematopoiesis.

Our findings suggest that TIGIT and CD96 could be markers of the clinical stage and treatment response of HNSCC. Therefore, administering anti-TIGIT and anti-CD96 after radiotherapy may provide a novel approach for incorporating immunoradiotherapy into HNSCC treatment.

Collectively, our data provide novel molecular insights into the immunoregulatory role of CD155 and establish epitope-specific mAbs as valuable tools for studying immune checkpoint pathways. This study provides a framework for developing CD155-targeted immunotherapies and enhances the understanding of immune escape mechanisms in cancers.

Recent therapeutic advances, particularly Nectin-4-targeted ADCs, anti-TIGIT ICIs, and bispecific antibodies (BsAbs), underscore their clinical promise. This review integrates current understanding of Nectin family members in oncogenesis and immunoregulation, focusing on their biological functions, mechanisms of immune modulation, therapeutic strategies, and remaining challenges in clinical translation.

The PVR-TIGIT/CD96/CD226 axis is a critical immune checkpoint in glioma. Targeted disruption of this pathway offers a promising strategy to overcome resistance and improve clinical outcomes.