Mechanistic roles and clinical applications of tertiary lymphoid structures in colorectal cancer drug resistance

Therapeutic resistance represents a formidable bottleneck in colorectal cancer (CRC) management, severely limiting the clinical efficacy of both conventional regimens and novel immunotherapies. Emerging evidence underscores tertiary lymphoid structure (TLS) - ectopic lymphoid aggregates newly sculpted within the tumor microenvironment (TME) - as pivotal orchestrators of localized antitumor immunity and prime therapeutic targets to circumvent resistance. Distinct from secondary lymphoid organs, TLS facilitate in situ immune cell priming, clonal expansion, and functional differentiation, thereby sustaining a robust adaptive immune response. This review systematically dissects the cellular architecture, maturation dynamics, and spatial heterogeneity of TLS in primary and metastatic CRC, clarifying how these attributes dictate clinical outcomes and treatment responsiveness. Mechanistically, we delineate the molecular networks driving TLS neogenesis, encompassing chemokine cascades, tumor necrosis factor (TNF) superfamily signaling, and interactive crosstalk with the gut microbiota. Furthermore, we summarize cutting-edge preclinical strategies - including stimulator of interferon genes agonists, bio-nanovaccines, and hypofractionated radiotherapy combinations - engineered to trigger TLS neogenesis, promote germinal center (GC) maturation, and enrich stem-like effector tumor-infiltrating lymphocytes (TILs) to convert immunologically “cold” tumors into “hot” niches. By integrating mechanistic paradigms with clinical applications, this review provides a definitive framework for leveraging TLS targeting as a transformative modality to modulate drug resistance and optimize therapeutic trajectories in CRC; the graphical abstract is shown below.