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

ABSTRACT 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 (TEXᵢnt) 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 (TEXₜerm) cells. Clonal tracking revealed that these Tfh and TEXᵢnt subsets possessed higher clonality, and in the complete responder, a dominant clone originating from the TEXᵢnt population persisted systemically by differentiating into a progenitor‐like (TEXₚrog) 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 TEXᵢnt subsets, defining a key cellular and clonal architecture for therapeutic success.