Vesicular QSOX1-MMP2 from inflammatory cancer-associated fibroblasts degrades the extracellular matrix to drive colorectal cancer pulmonary dissemination.

Pulmonary metastases represent a leading cause of mortality in colorectal cancer (CRC); however, the stromal mechanisms underlying metastatic colonization remain incompletely understood. Here, we show that extracellular vesicles (EVs) derived from inflammatory cancer-associated fibroblasts (iCAFs) are key promoters of CRC pulmonary metastasis (CRPM). Using single-cell RNA sequencing in a CRPM mouse model, we found that iCAFs constitute the predominant fibroblast population within the metastatic niche. Their differentiation was linked to NF-κB activation and SOCS3-mediated suppression of the TGF-β-Smad2/3 signaling pathway. Proteomic analysis further revealed selective enrichment of QSOX1 in iCAF-derived EVs. Functionally, QSOX1 binds to the N-terminal signal peptide (residues 1-29) of MMP2, suggesting that it may facilitate MMP2 secretion. Consistently, QSOX1 increased MMP2 abundance in EVs and enhanced EV-associated MMP2 activity, thereby facilitating degradation of the extracellular matrix (ECM) and enhancing the invasive capacity of CRC cells. Genetic knockdown of QSOX1 using siQsox1@LuT-LNPs, or its pharmacological inhibition with Ebselen, significantly reduced the lung metastatic burden and prolonged survival in vivo. Notably, Ebselen enhanced the anti-metastatic efficacy of anti-PD-L1 therapy to further suppress CRPM without augmenting toxicity. Our results establish EV-associated QSOX1-MMP2 as a pivotal regulator of metastatic niche remodeling and propose QSOX1 targeting, either alone or in combination with immune checkpoint blockade, as a promising therapeutic approach for CRPM.