SQYC formula improves the efficacy of PD-1 monoclonal antibodies in MSS colorectal cancer by regulating dendritic cell mitophagy via the PINK1-Parkin pathway

Abstract

Background: Microsatellite stable (MSS) colorectal carcinomas (CRCs) exhibit poor responsiveness to immunotherapy such as immune checkpoint inhibitors (ICIs). In the realm of clinical cancer treatment, traditional Chinese medicines (TCMs) are extensively utilized for their immunomodulatory properties. Shen Qi Yi Chang (SQYC), a clinical prescription for CRC treatment, improve the life quality of CRC patients and enhance their immune function.

Purpose: This study was to reveal the effect and mechanism of SQYC in improving the effect of PD-1 inhibitors in the treatment of MSS-type CRC.

Methods: CT26-luc in situ CRC tumor model and human CRC organoid model was established to evaluate the anti-tumor efficacy of SQYC combined with PD-1 inhibitor. Flow cytometry analysis was utilized to investigate the effect of SQYC on the infiltration and immune function of TILs and DCs in the immune microenvironment. Following this, RNA sequencing analysis, seahorse, TEM and immunofluorescence were performed to regulation of SQYC on mitophagy in DCs cells. UPLC-Q-TOF/MS and molecular docking were used to reveal the key blood-entering components of SQYC-regulated PINK1-parkin pathway.

Results: The SQYC-containing serum improved the efficacy of sintilimab in MSS CRC organoid model. After combined administration of 11.4 g/kg/day SQYC extract and 5 mg/kg α-PD-1, it was observed that SQYC enhanced the efficacy of PD-1 inhibitor against MSS CRC. Flow cytometry and immunofluorescence analysis revealed an augmented infiltration of tumor-infiltrating lymphocytes (TILs) and an improved antigen presentation function of dendritic cells (DCs). Notably, RNA sequencing analysis demonstrated an evident correlation with mitochondrial function related pathways following SQYC treatment. Mechanistically, SQYC promoted mitophagy in DCs via the PINK1-Parkin pathway, thereby improving mitochondrial quality, energy metabolism, and mitochondrial dynamics. Evaluation of the blood components of SQYC coupled with molecular docking, demonstrated good binding affinity with PINK1/PARKIN/LC3.

Conclusion: Our findings highlight SQYC as a promising candidate for improving immunotherapy in MSS CRC, suggesting that targeting PINK1-Parkin in DCs could represent a novel strategy for improving the efficacy of ICIs. Furthermore, it provides new theoretical and scientific underpinnings to enhance the clinical efficacy of immunosuppressants.

Keywords: DCs; MSS CRC; Mitophagy; PD-1 inhibitor; PINK1-Parkin; SQYC.