ObjectivesImmunotherapy yields limited results in patients with colorectal cancer (CRC), emphasizing the need for a deeper understanding of the immune landscape within the tumor microenvironment. Although the C-X-C motif chemokine ligand 13 (CXCL13) recruits B cells and promotes tertiary lymphoid structure (TLS) formation, its immune function and prognostic value in CRC remain unclear. This study investigated the impact of CXCL13 on patient outcomes and CRC immune landscape.MethodsFour independent cohorts were recruited in this study. The Cancer Genome Atlas Program (TCGA) cohort evaluated survival differences as well as immune contexture associated with CXCL13 expression in CRC. Immunohistochemistry (IHC) in the Renji Hospital (RJ) cohort was used to validate CXCL13 and CD8 levels, while multiplex IHC assessed their spatial correlation. Two single-cell RNA sequencing (scRNA-seq) cohorts were used for evaluating the potential roles of CXCL13 and CXCL13+CD8+T cells in the immune context of CRC.ResultsOur study revealed a positive correlation between CXCL13 expression and improved survival among CRC patients. Elevated CXCL13 levels and CXCL13+CD8+T cells were linked to a favorable immune context that impeded tumor growth in CRC. Moreover, CXCL13 expression was more prevalent in microsatellite instability-high (MSI-H)/mismatch repair-deficient (MMRd) tumors, demonstrating its potential role in enhancing the response to anti-programmed death-1 ligand (PD-L1) treatment.ConclusionsCXCL13 plays a critical role in shaping a favorable immune tumor microenvironment in CRC. Further research should elucidate how CXCL13 modulates CD8+T cell function to improve antitumor immunity.