Modulating pMMR colorectal tumors toward a dMMR-like phenotype by Xian-Lian-Jie-Du decoction enhances anti-PD-1 efficacy.

BACKGROUND

In advanced colorectal cancer (CRC), only approximately 5% of patients harbor deficient DNA mismatch repair (dMMR) tumors, which are responsive to immune checkpoint inhibitors (ICIs), whereas the remaining 95% with proficient mismatch repair (pMMR) derive limited benefit.

PURPOSE: To investigate whether the Chinese medicinal formulation Xian-Lian-Jie-Du decoction (XLJDD) can modulate pMMR colorectal tumors toward a dMMR-like phenotype, thereby enhancing their responsiveness to anti-PD-1 therapy.

STUDY

DESIGN

We employed an integrative approach using isogenic pMMR/dMMR mouse models, combining in vivo efficacy assessment, mechanistic dissection, and bioactive compound screening to elucidate how XLJDD overcomes immunotherapy resistance.

METHODS

We developed a pMMR/dMMR mouse model to assess the efficacy of XLJDD in conjunction with anti-PD-1 therapy. The therapeutic outcomes were examined using histopathological evaluation, immunofluorescence, and flow cytometry analyses. The mechanisms underlying XLJDD's effects were elucidated through transcriptomic, proteomic, and single-cell transcriptomic approaches. Additionally, ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) was employed to analyze the constituents of XLJDD.

RESULTS

We demonstrate that XLJDD sensitizes pMMR tumors to anti-PD-1 treatment, achieving efficacy comparable to that observed in dMMR tumors. Mechanistically, we reveal that pMMR tumor cells evade immune killing by downregulating and concealing interferon-gamma receptor 1 (IFNGR1) from the cell surface, thereby weakening interferon-gamma (IFN-γ) signaling. XLJDD overcomes this immune evasion by restoring IFNGR1 abundance and membrane localization, which amplifies IFN-γ-JAK2-STAT1 signaling and augments cytotoxic immune responses. We further identify Bilobalide A, an active component of XLJDD, as a critical factor in stabilizing IFNGR1 at the membrane and enhancing immunotherapeutic sensitivity in pMMR tumors.

CONCLUSION

These findings establish IFNGR1 expression and membrane localization as critical determinants of IFN-γ mediated tumor cell killing and identify XLJDD and its active component Bilobalide A as pharmacological strategies to target this pathway, providing a rationale for expanding the clinical benefit of anti-PD-1 therapy in pMMR CRC patients.