From Immunobiology to Clinical Application: Tumor-Infiltrating Lymphocytes in Melanoma

TL;DR

Tumor-infiltrating lymphocytes (TILs) are important in fighting melanoma and can be used as a treatment, showing promising results in patients who don't respond to other therapies.

Contribution

The paper reviews the biology, prognostic value, and clinical application of TILs in melanoma, emphasizing their role in adoptive cell therapy.

Findings

TILs and their interactions with myeloid cells influence tumor-fighting effectiveness in melanoma.

TIL-ACT achieves objective responses in 30–50% of patients who did not respond to immune checkpoint inhibitors.

Biomarkers and combination strategies are key to improving TIL therapy outcomes and accessibility.

Abstract

Background: Tumor-infiltrating lymphocytes (TILs) play a key role in the immune response against melanoma. They act as both markers of an active tumor environment and as treatments in adoptive cell therapy. This narrative review covers what is currently known about TIL biology, their prognostic and predictive value, and the use of TIL-based adoptive cell therapy (TIL-ACT) in advanced melanoma. Methods: We searched PubMed/MEDLINE, Web of Science and clinicaltrials.gov through January 2026 using terms related to melanoma, TILs, adoptive cell therapy, immune checkpoint inhibitors, neoantigens, T-cell receptor clonality, and spatial transcriptomics. We included original research, major clinical trials, translational studies and key reviews. Results: Melanoma often has many neoantigens, which leads to a high number of tumor-resident TILs. These TILs, their arrangement, and their interactions with myeloid cells influence how well they fight tumors. Features of TILs seen under the microscope and through other tests can help predict patient outcomes, even before treatment. Studies show that TIL-ACT leads to objective responses in about 30–50% of patients whose melanoma did not respond to immune checkpoint inhibitors. Some patients achieve lasting complete remissions, though the treatment can cause significant, mostly short-term side effects from lymphodepletion and interleukin-2. New research points to factors related to the patient, tumor, and TIL product that affect treatment success, supporting the use of biomarkers and combination strategies. Conclusions: TIL-based adoptive cell therapy is now a promising, personalized treatment for advanced melanoma after anti-PD-1 therapy has failed. Future studies should focus on identifying reliable biomarkers, improving TIL products, combining therapies to change the tumor environment, and making manufacturing more efficient to ensure more patients can safely access TIL therapy.

Figures