Tertiary lymphoid structures guided opportunities and challenges for immunotherapy in early gastroesophageal junction cancer and low rectal cancer.

Early-stage gastroesophageal junction cancer (GEJC) and low rectal cancer (LRC) pose a dilemma: surgery is often curative yet may cause lasting functional loss. Emerging data suggest that early tumors tend to exhibit an immune-active microenvironment with greater tertiary lymphoid structures (TLS) density and maturity, whereas advanced disease is frequently marked by immunosuppressive signaling, vascular and metabolic barriers, and attenuated TLS function. This review synthesizes stage-dependent immune ecology and evaluates how TLS biology may inform immunotherapy in early GEJC and LRC. We highlight opportunities for organ preservation in selected patients and key constraints: few trials in early-stage tumor, uncertain applicability beyond MSI-H or dMMR, limited performance of current biomarkers, challenges in assessing pathologic complete response, and the need for standardized surveillance when surgery is deferred. Overall, TLS-guided selection and rational microenvironment-modulating combinations appear promising, but replacing surgery should be confined to trials with rigorous endpoints and quality-of-life evaluation.