Exploring traditional Chinese medicine to enhance the efficacy and reduce toxicity of immunotherapy for non-small cell lung cancer from the perspective of "spleen deficiency": a trial protocol for mechanism and clinical evidence.

Introduction: Although immune checkpoint inhibitors (ICIs) have changed the treatment landscape of advanced non-small cell lung cancer (NSCLC), their low response rates and immune-related adverse reactions (irAEs) remain serious challenges. Traditional Chinese medicine believes that "spleen deficiency" is the core pathogenesis of advanced lung cancer, and its corresponding immune suppression and metabolic disorders may be related to the efficacy of ICIs. This paper aims to explore the clinical application status and potential mechanisms of traditional Chinese medicine combined with ICIs based on the "strengthening the spleen". Literature analysis shows that traditional Chinese medicines for invigorating spleen have shown positive trends in improving patients 'quality of life and reducing irAEs. Their mechanism of action may involve pathways such as regulating the "gut-lung axis" and reshaping the tumor immune microenvironment. However, this field still faces challenges such as the lack of high-quality randomized controlled trials, inconsistent dialectical standards, and unclear molecular mechanisms. Accordingly, we designed the present trial to explore the therapeutic efficacy and safety profile of JPGC combined with ICIs in patients with NSCLC. Methods/design: The evaluation design of the JPGC clinical trial was a randomized, double-blind, placebo-controlled study. The sample size is 56, and there are 28 participants in the test group and control group respectively. The test group received JPGC, and the control group received JPGC placebo. There is a course of treatment every 21 days for a total of 4 courses. The main outcomes include 6-month PFS rate, secondary outcomes include PFS, exploratory study endpoints include TCM syndrome integral, EORTC QLQ-C30, ECOG score, intestinal barrier, intestinal flora, inflammatory cytokines, T cell subsets, etc. Discussion: We predict that by repairing the intestinal barrier and adjusting the stability of intestinal flora to enhance the efficacy of immunotherapy for non-small cell lung cancer, non-small cell lung cancer patients will improve spleen deficiency and quality of life through JPGC. This study used TCM syndrome analysis, laboratory tests, imaging examinations and other indicators to evaluate the clinical efficacy and safety of JPGC. Fecal metabolomic analyses will be implemented in trial subjects to explore the latent synergistic mechanisms associated with JPGC intervention. This is a traditional Chinese medicine trial to observe and treat advanced NSCLC characterized by spleen deficiency syndrome by directly regulating intestinal flora. If successful, this discovery will have value in antitumor therapies and drug development, especially in the "immune era." Clinical Trial Registration: https://itmctr.ccebtcm.org.cn, identifier ITMCTR2025002090.