Lard-Based Diet Promotes Prostate Cancer Progression through Gut microbiota-Driven Immune Suppression in the Tumor Microenvironment

Growing epidemiological evidence indicates that dietary fats and obesity are linked to prostate cancer (PCa) progression. This study examines the impact of a lard-based diet (LD) on PCa progression through gut microbiota alterations and immune modulation. Using a prostate-specific Pten knockout mouse model, LD increased the relative abundance of the phylum Proteobacteria, which correlated with higher serum lipopolysaccharide (LPS) levels, weight gain, activation of TGF-β signaling, and accelerated PCa growth. Moreover, LD promoted Foxp3+ T cell infiltration within tumors, enhancing the immunosuppressive tumor microenvironment and driving cancer progression. Antibiotic treatment reduced both Foxp3+ T cell infiltration and serum LPS levels, highlighting the role of gut microbiota in PCa progression. Moreover, inhibiting LPS signaling suppressed high-fat diet-induced Foxp3+ T cell infiltration. In clinical samples, obesity was associated with increased FOXP3+ T cell infiltration in the prostate, while an abundance of gut class ε-Proteobacteria correlated with obesogenic phenotypes and advanced PCa features. These findings suggest that LD-induced gut microbiota changes and immune modulation contribute to PCa progression via systemic inflammation and intratumoral TGF-β signaling, presenting a potential preventive and therapeutic target for PCa.