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Abstract

Microsatellite stable (MSS) colorectal cancer (CRC) is often considered a “cold” tumor with limited response to programmed death-1 (PD-1) antibody monotherapy. The mechanisms underlying its intrinsic resistance to immunotherapy remain unclear. Here, we show that cathepsin D (CTSD) is highly expressed in MSS CRC and contributes significantly to immunotherapy resistance. Mechanistically, CTSD, acting as a protease, interacts with the α2 domain of the major histocompatibility complex (MHC) class I via the light chain of its catalytic domain, promoting MHC class I degradation through lysosomal pathways and impairing its recycling to the cell surface. This mechanism shields tumor cells from cytotoxic T-cell-mediated killing and facilitates immune evasion. Notably, genetic deletion or pharmacological inhibition of CTSD using pepstatin A prevents immune escape and enhances anti-PD-1 efficacy. These findings identify CTSD as a key mediator of immune evasion in MSS CRC and support the development of a combination therapy comprising CTSD inhibition and anti-PD-1 immunotherapy.