Tertiary lymphoid structures in luminal gastrointestinal cancers: biological circuits, spatial architecture, and biomarkers in the perioperative immunotherapy era

Tertiary lymphoid structures (TLS) are inducible, organized lymphoid clusters that recapitulate key functions of secondary lymphoid organs within chronically inflamed tumor tissue. In colorectal, gastric, and esophageal cancers, the most common luminal gastrointestinal (GI) malignancies, surgical resection preserves the spatial relationship between TLS and the tumor core, invasive margin, and surrounding mucosa, making the resected specimen a uniquely informative anchor for studying antitumor immunity. This narrative review synthesizes evidence from human cohorts, single-cell and spatial genomics, and perioperative immunotherapy trials. We trace the developmental continuum from loose lymphocytic clusters to germinal center-bearing follicles, contrast germinal center-dependent humoral immunity with germinal center-independent B-cell responses, and examine how regulatory T and B cells can turn TLS into immunosuppressive niches. We then analyze proposed inductive circuits, including chemokine-stromal organization, microbial and mutational antigenic pressure, and innate immune sensing, and discuss how desmoplasia, mechanical compression, hypoxia, and metabolic competition may arrest TLS maturation. A tumor-by-tumor comparison of colorectal, gastric, and esophageal cancers shows that TLS density, maturity, and anatomic localization carry divergent prognostic information; and diffuse gastric cancer, peritoneal metastases, and chemoradiated esophageal tumors illustrate states of TLS disruption. We also appraise neoadjuvant checkpoint trials (NICHE, NICHE-2, NEONIPIGA, CheckMate 577, MATTERHORN), consider TLS as complements to TNM staging for adjuvant decision-making and as candidate correlates of pathologic response, and outline experimental strategies for TLS induction and the technical prerequisites for translating TLS into surgical biomarkers. We hypothesize that mature, margin-positioned TLS are promising development- and location-dependent markers of organized antitumor immunity, but routine clinical use awaits standardized, multicenter validation. We therefore propose a minimum reporting framework to accelerate this translation.