This article presents a study utilizing spatial transcriptomics (Stereo-seq) to investigate the heterogeneity and developmental states of tertiary lymphoid structures (TLSs) in hepatocellular carcinoma (HCC) patients. The core finding is that tumor-derived tryptophan metabolism restricts the maturation of TLSs, classifying traditionally "immature" TLSs into distinct conforming and deviating types based on their potential for immune function and maturation. The research establishes that conforming TLSs correlate with better anti-tumor immunity and improved response to immune checkpoint blockade (ICB) therapy, suggesting that targeting tryptophan metabolism, potentially through TDO2 inhibitors or dietary restriction, could be a therapeutic strategy to promote TLS maturation and enhance anti-tumor responses. The study introduces a classification model to distinguish TLS subtypes and validates its findings across multiple cancer types and murine models.
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