Tumor Immune Microenvironment Biomarkers for Recurrence Prediction in Locally Advanced Rectal Cancer Patients after Neoadjuvant Chemoradiotherapy

Background/Objectives: The tumor microenvironment (TME) has emerged as a significant prognostic factor. This study aimed to identify prognostic factors by combining clinicopathologic parameters and the TME biomarkers in patients who underwent surgery following neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC). Methods: CD8(+) T cells, CXCR3, CXCL10, and alpha-smooth muscle actin (alpha-SMA) were analyzed via immunohistochemical staining. We also incorporated AI-powered digital pathology to assess the spatial TME. The associations between these biomarkers, clinicopathologic parameters, and survival outcomes were evaluated. Results: CD8(+) T cell expression, CXCR3 expression in tumor-infiltrating lymphocytes (TILs), and immune phenotypes were correlated. LARC patients with a high expression of CD8(+) T cells, CXCR3 in TILs, and an inflamed phenotype had a significantly better prognosis than their counterparts did. In the multivariate analysis, the expression of CD8(+) T cells and the inflamed/immune-excluded phenotype were significant tumor immune microenvironment (TiME) biomarkers for recurrence-free survival (RFS) but not for overall survival (OS). Notably, patients with the immune-desert phenotype had a poor prognosis regardless of pathologic stage, even if postoperative chemotherapy was administered (p < 0.001). Conclusions: CD8(+) T cells and AI-powered immune phenotypes, alongside clinical factors, can guide personalized treatment in LARC patients receiving nCRT. A therapeutic strategy to modify the TiME after nCRT could help reduce recurrence after surgery.