Orchestration of tertiary lymphoid structures: decoding developmental mechanisms for next-generation cancer immunotherapies

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that form in non-lymphoid organs, frequently observed in conditions such as cancer, autoimmune diseases, transplant rejection, and chronic inflammation. Growing evidence suggests that TLSs are beneficial for patients’ prognosis with higher TLS density generally correlating with improved therapeutic response and survival outcomes across malignancies and might serve as a novel therapeutic target for cancer immunotherapy. However, the correlation between TLSs and tumor development is still ambiguous. The exact timing of TLS formation during tumorigenesis and their dynamic evolution throughout tumor progression remain under investigation. Recent studies have identified potential strategies for inducing TLSs, but there remains a considerable distance from clinical application. More advanced techniques such as high-resolution spatial multi-omics technologies combined with big data analysis will benefit understanding the complex interactions within TLSs and developing novel immunotherapies.