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

An obesity-associated microbial signature enriched in riboflavin-producing taxa was identified in obese cancer patients who responded to immune checkpoint blockade (ICB).

• Obese responders to ICB showed enrichment in riboflavin-producing microbial taxa compared to non-responders
• Increased microbial riboflavin biosynthesis pathway activity was detected in obese responders
• Elevated levels of flavin adenine dinucleotide (FAD) were found in obese ICB responders
• This microbial signature was specifically associated with the obese responder subgroup, linking obesity, gut microbiota, and immunotherapy response

Fecal microbiota transplantation (FMT), administration of Lachnospiraceae bacterium, or FAD supplementation significantly enhanced anti-PD-1 therapy efficacy in diet-induced obese (DIO) mice.

• Experiments were conducted in diet-induced obese (DIO) mouse models
• All three interventions—FMT, Lachnospiraceae bacterium administration, and FAD supplementation—showed significant enhancement of anti-PD-1 therapeutic efficacy
• The enhancement of immunotherapy was specifically observed in the obese mouse model context
• These interventions collectively pointed to FAD as a key microbial metabolite mediating improved immunotherapy responses

FAD-based interventions increased the cytotoxicity of tumor-infiltrating CD8+ T cells via mesenteric adipocyte-driven synthesis of polyunsaturated fatty acids (PUFAs).

• The mechanism linking FAD to improved anti-tumor immunity involved mesenteric adipocytes as an intermediary
• Mesenteric adipocytes produced polyunsaturated fatty acids (PUFAs) in response to FAD signaling
• Increased PUFA synthesis was associated with enhanced CD8+ T cell cytotoxicity within tumors
• This established an axis from gut microbial metabolite FAD to adipose tissue lipid remodeling to tumor-infiltrating lymphocyte function

Inhibiting fatty acid desaturase 2 (FADS2) eliminated the immunotherapy benefits of FAD, demonstrating a critical role for adipocyte-intrinsic lipid remodeling.

• FADS2 is a key enzyme in the desaturation of fatty acids required for PUFA synthesis
• Pharmacological or genetic inhibition of FADS2 abolished the enhanced ICB efficacy conferred by FAD supplementation
• This finding identified FADS2-mediated adipocyte lipid remodeling as an essential mechanistic step in the FAD-to-immunity pathway
• The result underscored that the immunological benefit was dependent on adipocyte-intrinsic rather than systemic lipid metabolism

Elevated systemic levels of PUFAs, particularly docosahexaenoic acid (DHA), were positively correlated with intratumoral CD8+ T cell infiltration and favorable immunotherapy outcomes in clinical samples.

• Systemic PUFA levels were measured in cancer patients receiving immunotherapy
• DHA was specifically identified as a PUFA positively associated with improved clinical outcomes
• Higher circulating DHA correlated with greater intratumoral CD8+ T cell infiltration
• Elevated DHA levels were associated with favorable immunotherapy outcomes, providing clinical translational evidence for the microbiota-adipose-immunity axis

Dietary DHA supplementation improved ICB responses in lean mice, extending the therapeutic relevance beyond the obese phenotype.

• Lean (non-obese) mice were used in DHA dietary supplementation experiments
• DHA supplementation alone was sufficient to improve responses to immune checkpoint blockade
• This finding suggested that the PUFA-mediated immune enhancement is not restricted to obesity but may be broadly applicable
• The result supports potential dietary DHA supplementation as a strategy to augment ICB efficacy in non-obese cancer patients

Crosstalk between gut microbiota and adipose tissue was identified as a critical determinant of immunotherapy responses in cancer patients.

• The study establishes a 'microbiota-adipose axis' as a mechanistic framework for understanding variable ICB responses
• The axis involves gut microbial production of riboflavin/FAD, adipocyte lipid remodeling via FADS2, PUFA synthesis, and subsequent modulation of CD8+ T cell tumor infiltration and cytotoxicity
• The findings span both obese patient cohorts and preclinical mouse models
• The authors propose this axis enables 'potential personalized metabolic and microbial immunotherapy strategies'