Huang-Jin-Shuang-Shen Decoction promotes CD8+ T-cell-mediated anti-tumor immunity by regulating chemokine CXCL10 in gastric cancer

Background: Research on immunotherapy for gastric cancer is currently receiving significant attention, with particular emphasis on the role of CD8+ T cells in anti-tumor immune responses. In recent years, the importance of the chemokine CXCL10 in promoting anti-tumor immunity has been increasingly recognized because it plays a crucial role in recruiting CD8+ T cells to the tumor microenvironment. The Huang-Jin-Shuang-Shen (HJSS) Decoction, a Chinese medicine, has been used as an adjuvant drug for gastric cancer chemotherapy. Its mechanism of action may be related to the activation of anti-tumor immunity.

Purpose: To assess the role of the HJSS Decoction in regulating the immune microenvironment of gastric cancer and elucidate its mechanism.

Study design/methods: Ultra-high performance liquid chromatography Q Exactive-mass spectrometry was used to analyze the main components of the HJSS Decoction and evaluate the therapeutic effect of the HJSS Decoction synergized with 5-fluorouracil (5-FU) on gastric cancer. The proportions of CD8+ T cells and killing markers were determined using flow cytometry. Mechanisms of action and targets were screened using network pharmacology. The level of CXCL10 was detected using enzyme-linked immunosorbent assay and western blot, and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) related signaling pathway was detected in vitro. The target function was validated by siRNA transfection.

Results: The combination of HJSS Decoction and 5-FU demonstrated a synergistic effect in impeding the progression of subcutaneous gastric cancer. This was achieved through the facilitation of apoptosis and suppression of proliferation. Furthermore, HJSS Decoction exhibited the ability to enhance the population of CD8+ T cells and augment their cytotoxic capabilities, both in laboratory settings and in living organisms. Notably, HJSS Decoction upregulated the expression of CXCL10, and mechanistically, it activated the NFκB-related signaling pathway to initiate subsequent transcription of chemokines.

Conclusion: The present study aimed to investigate the pharmacological mechanism of the HJSS Decoction and its potential clinical application in inhibiting gastric cancer in mice. HJSS Decoction can cooperate with 5-FU to inhibit gastric cancer, and the optimal dose is medium. HJSS Decoction exerts anti-tumor immunity by activating the NFκB-related signaling pathway and promoting the expression of CXCL10, which in turn recruits CD8+ T cells into the tumor immune microenvironment. Overall, these findings provide valuable evidence for the potential clinical application of HJSS Decoction.