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Prior work has shown that a \u201cnatural ligand\u201d (NL)-based CAR targeting CD70, employing its physiological interaction partner CD27, may have therapeutic advantages over antibody- based CARs. Yet while antibody-based CARs are routinely optimized by affinity maturation of their scFv, whether the binding sequence of an NL CAR can be engineered to improve its function remains unexplored. Here, we combined deep learning with physics-based modeling to redesign residues at the CD27:CD70 interface, identifying a CD27 variant, \u201cN88A\u201d, which enhances the efficacy of CD70-targeting CAR T-cells across models of acute myeloid leukemia, multiple myeloma, and renal cell carcinoma. Biophysical approaches, including molecular dynamics simulations, support a mechanism of increased binder conformational freedom underlying potency enhancement. Our work presents CD27\n                  <jats:sub>N88A<\/jats:sub>\n                  CAR T-cells as a promising new therapeutic option and proposes that computational modeling could be applied to enhance efficacy of other NL-based immunotherapies.\n                <\/jats:p>","DOI":"10.64898\/2026.09.06.749651","type":"posted-content","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:55:15Z","timestamp":1789044915000},"source":"Crossref","is-referenced-by-count":0,"title":["Deep Learning-based Modeling Enhances Efficacy of Natural Ligand CAR Binders Targeting CD70"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0445-5654","authenticated-orcid":false,"given":"Amrik S","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA"},{"name":"Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA"},{"name":"Biomedical 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