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.