Recent Advances in Tumor-Infiltrating Lymphocyte Therapy for Melanoma

Melanoma is the most aggressive form of skin cancer and remains a leading cause of skin cancer-related mortality. The therapeutic landscape of melanoma has been revolutionized by the advent of immune checkpoint inhibitors (ICIs), resulting in significant improvements in patient survival. Nevertheless, treatment-related toxicities, resistance mechanisms, and disease progression remain major barriers to durable clinical benefit, highlighting an ongoing unmet medical need. Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a clinically active immunotherapeutic strategy for melanoma, particularly in patients with advanced or refractory disease. Continuous advances in biological understanding, manufacturing technologies, and clinical development have further strengthened its therapeutic potential. This review summarizes the biological basis of TIL therapy and outlines the manufacturing process from tumor procurement to lymphodepletion, TIL infusion, and interleukin-2 support. We then review current clinical evidence for conventional TIL products, including lifileucel, TM001, LM103, HS-IT101, and GC101, highlighting their efficacy and safety profiles. Emerging combination strategies integrating immune checkpoint inhibitors, targeted therapies, and oncolytic adenoviruses are also reviewed. In addition, advances in genetically engineered TILs, such as OBX-115, KSQ-001EX, and IOV-4001, are reviewed. Moreover, this review covers recent advances for improving therapeutic outcomes, including safety optimization, product optimization, next-generation engineered TILs, and predictive biomarkers. Challenges and future directions of TIL therapy in melanoma are also discussed. Overall, TIL therapy constitutes a rapidly evolving and clinically potent treatment modality for melanoma.