Traditional Chinese medicine enhances the effectiveness of immune checkpoint inhibitors in tumor treatment: A mechanism discussion.

Ethnopharmacological Relevance: Immune checkpoint inhibitors (ICIs) have altered the landscape of tumor immunotherapy, offering novel therapeutic approaches alongside surgery, chemotherapy, and radiotherapy and significantly improving survival benefits. However, their clinical efficacy is limited in some patients, and their use may cause immune-related adverse events (irAEs). Integrating traditional Chinese medicine (TCM) with ICIs has demonstrated the potential to boost sensitization and reduce toxicity. Clinical trials and experimental explorations have confirmed that TCM and its active components synergistically enhance the effectiveness of ICIs.

Aims: This narrative review summarizes the TCM practices that enhance the clinical efficacy and reduce irAEs of ICIs. This paper also summarizes the mechanism of experimental studies on the synergies of Chinese herbal decoctions, Chinese herbal preparation, and Chinese herbal active ingredients. Most of the studies on TCM combined with ICIs are basic experiments. We discussed the mechanism of TCM enhanced ICIs to provide reference for the research and development of TCM adjuvant immunotherapy.

Methods: We conducted a literature search using PubMed and Chinese National Knowledge Infrastructure databases, with a focus on herbal decoction, Chinese medicine preparations, and active ingredients that boost the effectiveness of ICIs and reduce irAEs. The search keywords were "ICIs and traditional Chinese medicine", "PD-1 and traditional Chinese medicine", "PD-L1 and traditional Chinese medicine", "CTLA-4 and traditional Chinese medicine", "IDO1 and traditional Chinese medicine", "Tim-3 and traditional Chinese medicine", "TIGIT and traditional Chinese medicine", "irAEs and traditional Chinese medicine". The search period was from May 2014 to May 2024. Articles involving the use of TCM or its components in combination with ICIs and investigating the underlying mechanisms were screened. Finally, 30 Chinese medicines used in combination with ICIs were obtained to explore the mechanism. In the part of immune checkpoint molecules other than PD-1, there were few studies on the combined application of TCM, so studies involving the regulation of immune checkpoint molecules by TCM were included.

Results: TCM has been shown to boost the effectiveness of ICIs and reduce irAEs. Researchers indicate that TCM and its active components can work synergistically with ICIs by regulating immune checkpoints PD-1, PD-L1, CTLA-4, and IDO1, regulating intestinal flora, improving tumor microenvironment and more.

Conclusions: Combining TCM with ICIs can play a better anti-tumor role, but larger samples and high-quality clinical trials are necessary to confirm this. Many Chinese medicines and their ingredients have been shown to sensitize ICIs in experimental studies, which provides a rich choice for the subsequent development of ICI enhancers.