CXCL13 + CD8 +  TILs–Mediated Metabolic–Immune Crosstalk Boosts Anti–PD-1 Efficacy via Tertiary Lymphoid Structure Neogenesis

Tumor-infiltrating lymphocytes (TILs) therapy represents a promising approach for the treatment of advanced melanoma, yet its efficacy is undermined by the abundance of bystander T cells lacking tumor specificity. Utilizing integrative multi-omics analyses, we found that CXCL13⁺CD8⁺ TILs as critical mediators of favorable prognosis and enhanced anti-PD-1 responsiveness. These specialized T cells recruit B cells via the CXCL13/CXCR5 axis, while reciprocally, activated B cells amplify CXCL13⁺CD8⁺ TILs function through TGF-β1/Smad2/3 signaling. Mechanistically, B cell-derived TGF-β1 induces dual reprogramming in CXCL13⁺CD8⁺ TILs: metabolic remodeling through arginine transporter upregulation, enhancing oxidative phosphorylation to fuel CXCL13 and cytotoxic molecule (GZMB/IFN-γ) production; and transcriptional activation via phospho-Smad3/Runx3 nuclear translocation, directly stimulating CXCL13 and effector gene expression. This bidirectional crosstalk establishes a self-reinforcing loop that drives tertiary lymphoid structure (TLS) assembly. Preclinically, adoptive transfer of CXCL13⁺CD8⁺ TILs demonstrated potent antitumor effects and synergy with PD-1 blockade. Our findings delineate a pivotal immunoregulatory circuit wherein CXCL13⁺CD8⁺ TILs and B cells mutually sustain effector functions through coupled metabolic and transcriptional reprogramming, ultimately fostering TLS development and robust antitumor immunity. These insights unveil new therapeutic avenues to enhance immunotherapy efficacy by amplifying this CXCL13⁺CD8⁺ TILs-B cell axis in melanoma and beyond.