T cell-mediated antibody-dependent cellular cytotoxicity provides a therapeutic approach for solid cancers

The clinical success of chimeric antigen receptor T cells in treating hematological malignancies has highlighted the immense therapeutic potential of engineering T cells with synthetic receptors. However, the limited availability of tumor-specific antigens and the poor ability of T cells to infiltrate solid tumor cores remain major obstacles for applying this approach to solid tumors. In this study, we identify a subset of CD8+ T cells at inflammatory sites that acquire FcγRI through trogocytosis from infiltrating monocytes, enabling them to perform transient TCR-independent antibody-dependent cellular cytotoxicity (ADCC). Analysis of FcγRI signaling in these T cells revealed that phosphorylation occurs only when antigen density on the membrane exceeds 30 molecules/μm². Exploiting this threshold, we engineered peripheral blood CD8+ T cells to express a modified FcγRI receptor, allowing them to selectively kill tumor cells while largely sparing healthy tissues expressing normal physiological levels of the same antigen. Moreover, expression of FcγRI receptor in T cells was associated with reduced basement membrane interactions, enhancing their capacity to infiltrate tumors and establish long-term immune memory. Collectively, this work establishes T cell-mediated ADCC as a potent therapeutic strategy that leverages antigen density, rather than antigen identity, to achieve selective cancer targeting.