An ICAM1-targeting chimeric costimulatory receptor mimics the immune synapse and enhances tumor-specific T cell function.

Engineered T cell therapies, such as chimeric antigen receptor (CAR) and T cell receptor (TCR)-based approaches, have transformed outcomes in hematological malignancies, yet their efficacy in solid tumors remains limited by tumor antigen escape, immunosuppressive microenvironments, and insufficient activation of CAR or TCR signaling. To overcome these barriers, we developed an intercellular adhesion molecule 1 (ICAM1)-specific chimeric costimulatory receptor (ICCR) engineered for expression in T cells to augment their activation. ICAM1 is broadly expressed across solid tumors and is further upregulated by IFNγ released during early T cell engagement, creating a feed-forward loop that reinforces tumor recognition. ICCR engagement with ICAM1 triggered NFκB signaling independently of TCR-p/MHC engagement; however, full T cell activation and cytotoxic function remained dependent on intact TCR signaling. In primary T cells, ICCR increased proliferation, cytokine production, and cytotoxicity, resulting in improved tumor control in two anaplastic thyroid cancer xenograft models treated with allogeneic or autologous ICCR-T cells. Mechanistically, ICCR strengthened tumor cell engagement, promoted selection and expansion of tumor-specific TCR clonotypes, and amplified downstream signaling pathways. These findings identify ICCR as a strategy that leverages an immune synapse-mimetic mechanism to enhance the function of low-activity tumor-specific TCRs and improve T cell responses in solid tumor microenvironments.