Evaluation of efficacy, safety and underlying mechanism on Traditional Chinese medicine as synergistic agents for cancer immunotherapy: A preclinical systematic review and meta-analysis.

Ethnopharmacological Relevance: Based on the documentation in Shennong's Herbal Classics, numerous Traditional Chinese medicine (TCM) are noted to possess anti-tumor properties, and TCM has been used in China for thousands of years. Particularly, current research have demonstrated that TCM combined with immunotherapy exhibited enhanced anti-tumor effects.

Aim Of The Study: This meta-analysis aimed to evaluate the effectiveness, security, and potential mechanisms of TCM coupled with programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) inhibitors in cancer animal models.

Materials And Methods: The pertinent research was performed in English database including PubMed, Web of Science, Embase, and Cochrane Library, as well as Chinese database including China National Knowledge Infrastructure (CNKI) and Wanfang Data Database published until January 2024. The quality of the included studies was evaluated with Systematic Review Center for Laboratory animal Experimentation (SYRCLE) risk assessment tool, and statistical analysis was conducted with Revman 5.4 software. Egger's test and funnel plots were used to assess potential publication bias.

Results: An aggregate of 30 articles comprising 39 studies fulfilled the conditions for examination. The meta-analysis revealed that TCM + PD-1/PD-L1 inhibitors exhibited significant effects in inhibiting tumor growth (standard mean difference (SMD) = -2.61, 95% confidence interval (CI) = [-3.15, -2.07]), reducing tumor weight [SMD = -2.79 (-3.75, -1.83)], prolonging the survival time, and enhancing immune function in both cellular (CD4 T cell percentage: 3.00 [1.45, 4.55]; CD8 T cell percentage: 3.06 [2.16, 3.95]) and humoral immunity (interferon-γ (IFN-γ): 3.43, [2.54, 4.32]; tumor necrosis factor-α (TNF-α): 2.78 [1.46, 4.09]; interleukin (IL)-2: 1.79, [0.62, 2.95]; IL-6: 2.34, [0.07, 4.60]), and the differences between the two groups of the above indicators were statistically significant. No significant difference was found for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. The mechanisms of TCM impacting PD-1/PD-L1 inhibitors therapy were closely associated with regulating tumor microenvironment, modulating gut microbiota, suppressing expression of PD-1 or PD-L1, and regulating cytokine signaling.

Conclusion: TCM displayed a potential enhanced anti-tumor efficacy of PD-1/PD-L1 inhibitors on six types of tumor including colon, breast, colorectal, melanoma, and bladder cancer in animals. However, due to significant heterogeneity in the included studies, caution should be exercised regarding the results. More high-quality randomized controlled animal experiments are need.