Impaired autophagy by cepharanthine induces immunogenic cell death and enhances anti-PD-1 response in MSS-type colorectal cancer.

Abstract

Blockade of the PD-1/PD-L1 axis has demonstrated remarkable success in treating colorectal cancer (CRC) with high microsatellite instability (MSI-H). However, the metastatic CRC with microsatellite stability (MSS) does not respond to this approach. A recent study revealed that rare neoantigens in MSS-type CRC cells can be recognized by antigen-specific CD8+ T cells but not by dendritic cells (DCs). Thus, increasing neoantigen availability by DCs may improve the efficacy of PD-1/PD-L1 inhibitors in MSS-type CRC. Here, we conducted a drug library screening for 'eat me' signal, represented by cell surface calreticulin (CRT) exposure, in MSS-type CT26 cells. Cells treated with identified cepharanthine (CEP) presented hallmarks of immunogenic cell death (ICD), characterized by increased cell surface CRT exposure, the release of HMGB1 and ATP, increased susceptibility to phagocytosis, and the ability of vaccines to elicit immunogenic potential in vivo. Mechanistically, CEP blocked autophagic flux by inhibiting autophagsome-lysosome fusion, leading to endoplasmic reticulum (ER) stress and ICD activation. Moreover, CEP upregulated PD-L1 expression on tumour cells, impeding the antitumour immune response in vivo. The combination of CEP and anti-PD-1 therapy provided therapeutic benefit to MSS-type CRC tumours, with an increased proportion of activated DCs and IFNγ⁺ CD8⁺ T cells and a decreased proportion of regulatory T cells within the tumour. Based on the above observation, subsequent clinical trials can be conducted to achieve the clinical goal of increasing the survival benefit of MSS-CRC patients.