Single-Cell Dissection of Tumor-Infiltrating Lymphocytes Reveals Cellular Architecture Predictive of Therapeutic Efficacy in Acral Melanoma.

Acral melanoma (AM), the predominant melanoma subtype in Asia, responds poorly to immune checkpoint inhibitors, representing a critical unmet medical need. The efficacy of tumor-infiltrating lymphocyte (TIL) therapy in this population is unknown. An Investigator-Initiated Trial evaluates autologous TIL therapy (LM-103) in four Chinese patients with advanced AM, achieving a 75% disease control rate (DCR) and a 25% objective response rate (ORR), including one durable complete response. To define the determinants of response, we performed integrated single-cell RNA and T-cell receptor sequencing on infused TIL products, tumors, and longitudinal peripheral blood. Responders' infused products were significantly enriched for T follicular helper (Tfh) and intermediate exhausted (TEX_int) CD8⁺ T cells, which mediated robust cell-cell signaling networks (e.g., CD40, FASLG). In contrast, the non-responder's product was dominated by terminally exhausted (TEX_term) cells. Clonal tracking revealed that these Tfh and TEX_int subsets possessed higher clonality, and in the complete responder, a dominant clone originating from the TEX_int population persisted systemically by differentiating into a progenitor-like (TEX_prog) state. These findings demonstrate that TIL therapy is clinically active in AM and that durable response is mechanistically linked to the infusion and persistence of Tfh and TEX_int subsets, defining a key cellular and clonal architecture for therapeutic success.