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

Abstract

Background: We have reported that chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR) are effective in a preclinical model of triple negative breast cancer (TNBC), and have initiated a Phase I study to assess safety and efficacy. However, heterogeneous antigen expression and immunosuppressive tumor microenvironments (TME) remain roadblocks for effective CAR-T cell therapy. In particular, obesity represents a negative prognostic factor in TNBC partly due to chronic inflammation and impaired adaptive immune responses. Hence, we sought to determine if obesity can affect the antitumor activity of B7-H3.CAR-T cells. Methods: We used qPCR and western blotting to determine if cytokines associated with obesity affect B7-H3 expression in TNBC cell lines. Furthermore, we used shRNA to suppress B7-H3 expression in a syngeneic orthotopic E0771 tumor model and measured tumor growth in control and diet-induced obese (DIO) mice. Finally, we evaluated the antitumor effects of B7-H3.CAR-T cells in both control and DIO mice orthotopically engrafted with the E0771 tumor cell line. Immune profiling was conducted using flow cytometry. Results: ) and impaired glycolytic capacity, respectively. Finally, we demonstrated that obesity impairs CAR-T cell antitumor effects and durability of response in vivo with a near complete loss of memory formation. Conclusions: Here we identified a correlation between B7-H3 expression, obesity, and rate of tumor growth in TNBC. Furthermore, we showed that obesity constrains both the ability of B7-H3.CAR-T cells to control tumor growth and to elicit durable immunological memory. Taken together, these data identify obesity as an underappreciated and potent modulator of CAR-T cell functionality. What is already known: B7-H3 protein is upregulated in many human malignancies including TNBC and is often associated with worsened outcomes. B7-H3.CAR-T cells show promise in preclinical models of TNBC and entered clinical translation. What this study adds: This study identifies a previously unknown correlation between obesity, B7-H3 expression, and rate of tumor growth in TNBC. Furthermore, our preclinical model of B7-H3.CAR-T cell therapy demonstrates that obesity negatively affects the antitumor activity of B7-H3.CAR-T cells in TNBC. How this study affects other research/practice: This study highlights obesity as an understudied and critically important covariate for adoptive T-cell therapy and demonstrates important links between systemic metabolism and antigen expression. This work paves the way for future mechanistic and translational research into how obesity impacts CAR-T cell functionality.

The authors' abstract, as published at the source. npj Breast Cancer, 2026 · DOI ↗