Background <p>Immune checkpoint inhibitors demonstrate high efficacy in MSI-H/dMMR colorectal cancer, yet a subset of patients develops resistance. This case reports in situ recurrence in Lynch syndrome-associated colon cancer, with the novel observation that while the recurrent lesion responded completely to immunotherapy, a concurrent dMMR ascending colon adenoma showed resistance.</p> Case presentation <p>A patient with Lynch syndrome-associated colon cancer experienced in situ recurrence. Immunotherapy led to complete response in the recurrent lesion, but the coexisting dMMR ascending colon adenoma failed to respond. Multiplex immunofluorescence and whole-exome sequencing revealed high CD68⁺ macrophage infiltration, low CD8⁺ T cells, CD20⁺ B cells, and CD56⁺ NK cells in the adenoma, along with mutations in NRAS, CTNNB1, HLA-DQB1/DRB1/DRB5, VEGFA, TGFBI, PTGS2, and others.</p> Conclusion <p>This case highlights marked heterogeneity in immunotherapy responses among dMMR colorectal cancer patients. Even sustained responders require ongoing colonoscopic surveillance and polypectomy when indicated, particularly those with a history of polyps. Tumor microenvironment features and specific mutations may contribute to immune escape.</p>