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Cathepsin D-Mediated MHC-I Degradation Contributes to Immune Evasion in Microsatellite Stable Colorectal Cancer

ABSTRACT: Microsatellite stable (MSS) colorectal cancer (CRC) is often characterized as a "cold" tumor, exhibiting minimal responsiveness to monotherapy with PD-1 antibodies. The underlying mechanisms of this intrinsic unresponsiveness to immunotherapy have been elusive. Here, we report that cathepsin D (CTSD) is highly expressed in MSS CRC, significantly contributing to its resistance to immunotherapy. Specifically, CTSD facilitates immune evasion by shielding cancer cells from cytotoxic T-cell-mediated killing. Mechanistically, as a protease, CTSD interacts with the α2 domain of the major histocompatibility complex class I (MHC-I) molecule via its catalytic domain's light chain, promoting the degradation of MHC-I through lysosomal pathways and disrupting the recycling of MHC-I to the cell surface. Notably, deletion or pharmacological inhibition of CTSD with pepstatin A prevents this immune evasion and enhances the efficacy of anti-PD-1 antibodies. Collectively, these findings highlight the role of CTSD in immune evasion and provide a compelling rationale for the development of a novel combination therapy involving CTSD inhibition and anti-PD-1 immunotherapy in CRC.

ORGANISM(S): Mus musculus

PROVIDER: GSE306871 | GEO | 2025/10/18

REPOSITORIES: GEO

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Project description:Patients with the microsatellite stable (MSS) subset of colorectal cancer, which accounts for 85-90% of all human colorectal cancer cases, do not respond to PD-(L)1 immune checkpoint inhibitor immunotherapy. Metastasis accounts for over 90% of human colorectal cancer mortality and liver metastasis accounts for 90% of human colorectal cancer metastasis. The mechanism underlying colorectal tumor cell immune evasion and the resultant liver metastasis is incompletely understood. The SUV39H1-H3K9me3 epigenetic pathway has emerged as a key regulator of CTL persistence and effector function in anti-tumor immunity. We therefore aimed at testing the hypothesis that H3K9me3 induces CTL dysfunction to promote colorectal tumor liver metastasis. Using a mouse MSS colon tumor experimental liver metastasis model, we observed that PD-1 blockade immunotherapy does not induce CTL activation in the liver metastases and exhibits no significant efficacy in suppression of liver metastasis. CTL adaptive transfer increased accumulation of the tumor-specific CTLs in liver metastases but also exhibited no significant efficacy in suppression of liver metastasis. However, pharmacological inhibition of H3K9me3-specific histone methyltransferases with the small molecule F5446 significantly suppressed liver metastasis in mice. scRNA-seq analysis of liver metastases-infiltrating immune cells revealed that F5446 therapy does not increased total level of T cell tumor infiltration. Instead, inhibition of H3K9me3 increased Tex and decreased Tcm in liver metastases. Analysis of human colon tumor scRNA-Seq datasets identified Tex, Tcm and Tem-like clusters in both primary and liver metastasis with higher level of Tex subset of T cells in liver metastases than primary tumor. Our findings determine that colon tumor cells induce H3K9me3 to regulate T cell differentiation and effector function in liver metastases microenvironment and targeting H3K9me3 is a promising approach for suppression of CRC liver metastasis.

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Cathepsin D-Mediated MHC-I Degradation Contributes to Immune Evasion in Microsatellite Stable Colorectal Cancer

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