Chimeric antigen receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies, but poor specificity has limited its applicability to solid tumors. By contrast, natural T cells harboring T cell receptors (TCRs) can discriminate between neoantigen-expressing cancer cells and self-antigen-expressing healthy tissues but have limited potency against tumors. We used a high-throughput platform to systematically evaluate the impact of co-expressing a TCR and CAR on the same CAR T cell. While strong TCR-antigen interactions enhanced CAR activation, weak TCR-antigen interactions actively antagonized their activation. Mathematical modeling captured this TCR-CAR crosstalk in CAR T cells, allowing us to engineer dual TCR/CAR T cells targeting neoantigens (HHATL8F/p53R175H) and human epithelial growth factor receptor 2 (HER2) ligands, respectively. These T cells exhibited superior anti-cancer activity and minimal toxicity against healthy tissue compared with conventional CAR T cells in a humanized solid tumor mouse model. Harnessing pre-existing inhibitory crosstalk between receptors, therefore, paves the way for the design of more precise cancer immunotherapies.

Sooraj Achar is a DPhil candidate in Biomedical Sciences associated with the NIH/Oxford graduate partnership program, conducting research at the intersection of immunology and systems biology under the joint mentorship of Dr. Gregoire Altan-Bonnet (NCI) and Prof. Michael Dustin (Kennedy Institute of Rheumatology). He holds a B.S. in Biochemistry and a Mathematics minor from the University of Virginia. Sooraj’s work on how T cells respond to diverse antigenic signals has led to multiple high-impact publications in journals such as Science, Cell, and Nature Immunology. He is the recipient of several awards, including the 2025 Peter Medawar Prize for Immunology and the 2023 Bill Paul Award for Cytokine Research.