Microbial metabolite FAD mobilizes adipocyte lipid remodeling to enhance cancer immunotherapy efficacy.

Abstract

Crosstalk between gut microbiota and adipose tissue critically shapes immunotherapy responses in patients with cancer. An obesity-associated microbial signature enriched in riboflavin-producing taxa was identified, along with increased microbial riboflavin biosynthesis pathway and elevated levels of flavin adenine dinucleotide (FAD), in obese responders to immune checkpoint blockade (ICB). In diet-induced obese (DIO) mice, fecal microbiota transplantation (FMT), administration of Lachnospiraceae bacterium, or FAD supplementation significantly enhanced the therapeutic efficacy of anti-PD-1 therapy. These interventions increased the cytotoxicity of tumor-infiltrating CD8⁺ T cells via mesenteric adipocyte-driven synthesis of polyunsaturated fatty acids (PUFAs). Inhibiting fatty acid desaturase 2 (FADS2) eliminated the benefits of FAD, underscoring a critical role for adipocyte-intrinsic lipid remodeling in mediating immune responses. Clinically, elevated systemic levels of PUFAs, particularly docosahexaenoic acid (DHA), were positively correlated with intratumoral CD8⁺ T cell infiltration and favorable immunotherapy outcomes. Dietary DHA supplementation improved ICB responses in lean mice. This study highlights that a microbiota-adipose axis shapes antitumor immunity, enabling potential personalized metabolic and microbial immunotherapy strategies.