Hepatic metastasis secondary to colorectal cancer (CRC) remains a formidable clinical problem that dramatically shortens patient survival. Myofibroblastic cancer-associated fibroblasts (myCAFs) are among the most abundant stromal populations in the CRC tumor microenvironment and actively facilitate tumor growth and metastatic colonization by secreting exosomes. Single-cell profiling demonstrated a prominent accumulation of myCAFs within colorectal cancer liver metastases (CRLM). Sequencing of exosomal cargo revealed PWAR6 as the long non-coding RNA (lncRNA) showing the highest degree of upregulation in metastatic lesions. Complementary in vitro and in vivo experiments established that PWAR6 drives CRC cell stemness, motility, and glutamine acquisition. The underlying molecular pathway was dissected using RNA pulldown, RIP, and Co-IP assays focused on the PWAR6/NRF2/SLC38A2 axis in CRC progression, while flow cytometry quantified NK cell effector functions and cytotoxic potential. Clinically, elevated PWAR6 expression showed a robust association with higher 68Ga FAPI-PET/CT SUVmax values, particularly in patients with CRLM, where transcript levels were markedly higher than in non-metastatic cases and in normal colonic mucosa. Both regression modeling and survival analyses identified PWAR6 as an independent predictor of poor prognosis, with higher expression associated with inferior clinical outcomes. Mechanistically, PWAR6 enables immune escape by competitively binding Keap1, thereby stabilizing NRF2, which transcriptionally induces SLC38A2. The resulting increase in glutamine uptake by CRC cells simultaneously restricts glutamine availability to NK cells. Exosomal PWAR6 released by myCAFs acts as a central biomarker of CRC liver metastasis. Its specific inhibition by ASO-PWAR6, when combined with FAPI therapy, substantially attenuates metastatic progression in preclinical models and holds considerable promise for future clinical practice.
