Shenling Baizhu Powder potentiates immunotherapy response: putative roles of gut microbial remodeling and fatty acid metabolism modulation.

[BACKGROUND] Low response rates and immune-related adverse events (irAEs) are major factors affecting the efficacy of PD-1 monoclonal antibody (mAb) immunotherapy in NSCLC. Modulating the gut microbiota-immune-tumor axis is considered a key strategy to overcome these challenges.

[PURPOSE] This study aimed to investigate whether Shenling Baizhu powder (SLBZS), a traditional Chinese medicine formula, could enhance the efficacy of PD-1 mAb immunotherapy and mitigate irAEs by regulating gut microbiota and host metabolism.

[STUDY DESIGN] Two experimental models were employed: (1) a standard Lewis subcutaneous tumor mouse model to evaluate therapeutic effects and irAEs, and (2) a lung metastasis model using bioluminescence imaging to assess tumor progression. Additionally, an antibiotic-cleared mouse model combined with fecal microbiota transplantation (FMT) was used to validate gut microbiota-mediated mechanisms.

[METHODS] Subcutaneous tumor growth, organ toxicity, and metastasis were monitored in vivo. Multi-omics approaches included fecal 16S rDNA sequencing, untargeted/targeted plasma metabolomics, and immune profiling of splenic and tumor microenvironment (TME) lymphocytes. SLBZS/FMT interventions were applied to antibiotic-treated mice to assess microbiota-dependent effects.

[RESULTS] SLBZS synergized with PD-1 mAb to significantly inhibit tumor growth and reduce multi-organ irAEs. In the metastasis model, SLBZS suppressed early tumor implantation and late-stage dissemination. Multi-omics analyses revealed that SLBZS enriched beneficial gut bacteria (e.g., Akkermansia, Lactobacillus, Muribaculum) and microbial metabolites, including short-chain fatty acids (SCFAs), while enhancing anti-tumor T-cell subsets in the spleen and TME. Critically, SLBZS/FMT restored gut microbiota homeostasis and reversed antibiotic-induced immunotherapy resistance.

[CONCLUSION] SLBZS, as a traditional Chinese medicinal formulation, enhances the efficacy of PD-1 mAb through a unique dual-regulatory mechanism. It concurrently remodels the gut microbiota structure and optimizes the metabolic microenvironment, with these synergistic actions collectively amplifying anti-tumor immunity while reducing irAEs. This dual-mode efficacy distinguishes SLBZS from conventional microbial modulators that solely target microbiota without metabolic coordination. Our study provides the first experimental validation of SLBZS as a clinically valuable adjuvant of Chinese medicinal origin for NSCLC immunotherapy. Furthermore, we pioneer a novel research paradigm integrating traditional Chinese medical theory with the "microbiota-metabolism-immune network" axis, thereby offering innovative therapeutic strategies for refining cancer immunotherapies.