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However, it is still unclear which patients would benefit from AXL-targeting therapies. We conducted a clinical and molecular characterization of\n                      <jats:italic>AXL<\/jats:italic>\n                      in colorectal cancer (CRC).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study integrated real-world molecular profiling (Caris cohort; n=24,257) and randomized clinical trial data (phase III Cancer and Leukemia Group B\/Southwest Oncology Group (CALGB\/SWOG) 80405; n=433) to assess\n                      <jats:italic>AXL<\/jats:italic>\n                      messenger RNA expression in patients with CRC. Tumor samples underwent RNA sequencing and analysis of the immune microenvironment.\n                      <jats:italic>AXL<\/jats:italic>\n                      expression was categorized into tertiles. We assessed associations between molecular features, immune biomarkers, and clinical outcomes, including overall survival (OS) and progression-free survival (PFS), using Kaplan-Meier and Cox proportional hazards models while adjusting for relevant covariates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Elevated\n                      <jats:italic>AXL<\/jats:italic>\n                      expression correlated with increased programmed death-ligand 1 immunohistochemistry positivity (6.2% vs 2.5%, q&lt;0.0001), immune checkpoint-related gene expression, and infiltration of immunosuppressive cell populations (T-regulatory cells, M2 macrophages, monocytes, and B cells). Pathway analyses demonstrated links between high\n                      <jats:italic>AXL<\/jats:italic>\n                      expression and epithelial\u2013mesenchymal transition, inflammatory signaling, interferon-gamma response, and tumor necrosis factor alpha signaling. In the Caris cohort, high\n                      <jats:italic>AXL<\/jats:italic>\n                      predicted worse OS in patients treated with fluorouracil, leucovorin, and oxaliplatin\/fluorouracil, leucovorin, and irinotecan (38.0 vs 34.7\u2009months, p=0.027; HR 1.07), bevacizumab (36.8 vs 32.6\u2009months, p=0.013; HR 1.21), and anti-epidermal growth factor receptor therapy (28.4 vs 22.2\u2009months, p=0.005; HR 1.21), but profoundly improved OS in\n                      <jats:italic>KRAS<\/jats:italic>\n                      mutant patients treated with immunotherapy (11.6 vs 23.4\u2009months, p=0.012; HR 0.65). CALGB\/SWOG 80405 findings confirmed shorter PFS (9.2 vs 12.9\u2009months, p=0.001; HR 1.56) and OS (24.2 vs 34.7\u2009months, p&lt;0.001; HR 1.68) with high\n                      <jats:italic>AXL<\/jats:italic>\n                      expression across treatment arms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Elevated\n                      <jats:italic>AXL<\/jats:italic>\n                      expression in CRC correlated with an immunosuppressive microenvironment and worse outcomes across standard treatments. However, it identifies a distinct subgroup of\n                      <jats:italic>KRAS<\/jats:italic>\n                      -mutant patients who significantly benefit from immunotherapy, supporting\n                      <jats:italic>AXL<\/jats:italic>\n                      as a context-specific biomarker and therapeutic target.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013186","type":"journal-article","created":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T19:10:18Z","timestamp":1766344218000},"page":"e013186","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical and molecular characterization of\n                    <i>AXL<\/i>\n                    in colorectal cancer, CALGB (Alliance)\/SWOG 80405 and real-world 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