Synthetic Nanobiology Actuated Lipometabolic Cell Factory for Autologous Tumor Immunotherapy

Abstract Dysregulated fatty acid (FA) metabolism in the tumor microenvironment induces immunosuppression, which significantly promotes tumor progression and compromises immunotherapy. Sptlc2‐mediated FA‐ceramide biosynthesis exhibits potent immune activation and anti‐tumor efficacy. However, Sptlc2 expression deficiency, ceramide‐dependent feedback inhibition, and nonspecific lipotoxicity limit its clinical application. Herein, an FA ‐ Ce ramide S ynthetic nanobiology (FACES) cell factory is developed encapsulating Sptlc2‐I503R plasmids (Sptlc2 mut ) and CPT1a inhibitor (etomoxir) within a zinc zeolitic imidazolate framework (ZIF‐8). The etomoxir‐mediated FA accumulation provides abundant materials for ceramide biosynthesis, and Sptlc2 mut abolishes the feedback inhibition by excessive ceramide. Hence, the FACES cell factory represses tumor progression by restricting energy supply and facilitating lipotoxicity. Furthermore, FACES elicits autologous systemic anti‐tumor immunity via paracrine ceramide production. Overall, the FACES cell factory, designed based on a synthetic nanobiology strategy, remodels dysregulated FA metabolism to activate autologous systemic anti‐tumor immunity and suppresses tumor growth, providing a promising strategy for specific and safe tumor treatment.