Obesity impairs the antitumor activity of CAR-T cells in triple-negative breast cancer

Chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR) have demonstrated efficacy in preclinical models of triple-negative breast cancer (TNBC), prompting the initiation of a Phase I clinical trial to evaluate safety and efficacy. However, heterogeneous antigen expression and immunosuppressive tumor microenvironments (TME) remain significant obstacles to effective CAR-T cell therapy. Obesity represents a negative prognostic factor in TNBC, attributable in part to chronic inflammation and impaired adaptive immune responses. Therefore, we investigated whether obesity influences the antitumor activity of B7-H3.CAR-T cells. Obesity-associated inflammatory cytokines upregulated B7-H3 expression in human and murine TNBC cells in vitro, and B7-H3 expression was required for obesity to promote TNBC tumor growth in vivo. CAR-T cells derived from control or diet-induced obese (DIO) mice exhibited equivalent cytotoxicity in vitro; however, activated T cells and B7-H3.CAR-T cells obtained from DIO mice demonstrated transcriptomic alterations and diminished glycolytic capacity, respectively. Obesity significantly impaired CAR-T cell antitumor activity and durability of response in vivo, with a near-complete abrogation of tissue-resident memory T cell formation. These findings demonstrate that obesity constrains both the ability of B7-H3.CAR-T cells to control tumor growth and to elicit immunological memory, and that obesity requires B7-H3 to enable immune evasion and TNBC progression.