Engineered Immune Cells Push Melanoma Therapy Into a New Era

Melanoma remains one of the most aggressive human cancers, arising from the pigment-producing melanocytes of the skin and, less commonly, from mucosal membranes and ocular tissues. Although surgical excision cures many patients whose disease is caught early, melanoma has a notorious propensity for early invasion and distant spread. Once advanced, the outlook has historically been grim: median survival of only six to nine months, a three-year survival rate below fifteen percent, and recurrence rates approaching sixty percent. The global burden is also growing, with incidence rising by roughly two to three percent each year and an estimated 324,600 new cases and 57,000 deaths worldwide annually. A comprehensive new review published in Clinical Cancer Bulletin by researchers at Zhongshan Hospital, Fudan University, examines how adoptive cell therapy, or ACT, is reshaping this landscape and where the field must go next.

ACT is a form of precision immunotherapy in which a patient’s own immune cells are extracted, expanded or genetically modified in the laboratory to sharpen their tumor-killing capacity, and then reinfused into the body. The approach encompasses several distinct modalities: tumor-infiltrating lymphocyte therapy, chimeric antigen receptor T cell therapy, T cell receptor-engineered T cell therapy, and emerging strategies built on natural killer cells, dendritic cells, and gamma-delta T cells. The review arrives at a pivotal moment. Targeted therapies against BRAF and NRAS mutations and immune checkpoint inhibitors targeting PD-1 and CTLA-4 have already transformed advanced melanoma care, with pembrolizumab demonstrating an objective response rate of fifty-six percent after its 2014 approval. Yet nearly half of patients either resist these drugs from the start or acquire resistance during treatment, leaving an urgent need for more durable options.

The clearest success story belongs to TIL therapy, which harvests lymphocytes that have already infiltrated a patient’s tumor, expands them massively in culture, and returns them after a round of non-myeloablative lymphodepleting chemotherapy followed by several days of interleukin-2 support. Pioneered clinically by Steven Rosenberg in the 1980s, the approach exploits melanoma’s high mutational burden and dense immune infiltration. A systematic analysis of thirteen trials conducted between 1988 and 2016 found an overall response rate of forty-one percent, with fourteen percent of patients achieving complete responses, among 410 advanced melanoma patients treated with TILs plus interleukin-2. More recent data have been equally striking: a multicenter Phase II trial reported an objective response rate of 31.4 percent among 153 patients whose disease had resisted immunotherapy, with survival rates of 54 percent at one year and nearly 22 percent at four years.

Those results culminated in a historic milestone. On February 16, 2024, lifileucel, a TIL product developed by Iovance Biotherapeutics, became the first TIL-based therapy ever approved by the U.S. Food and Drug Administration, indicated for advanced melanoma refractory to PD-1 or PD-L1 checkpoint inhibitors. A Phase III trial further strengthened the case, showing that TIL therapy achieved a forty-nine percent objective response rate and outperformed the CTLA-4 inhibitor ipilimumab in patients whose tumors had progressed on PD-1 blockade, while also improving quality of life and physical function. Even in uveal melanoma, a rare subtype notoriously resistant to immunotherapy, TIL therapy produced responses in thirty-five percent of patients. The review notes that TILs carry inherent advantages: their broad T cell receptor diversity allows them to recognize many tumor antigens simultaneously, reducing off-target toxicity, and their natural origin within the tumor confers superior homing ability compared with engineered cells directed at a single antigen.

TIL therapy is not without weaknesses, however. Prolonged exposure to tumor antigens can drive functional exhaustion in the very cells that matter most, and tumors harbor large populations of bystander T cells that recognize nothing and contribute little cytotoxic activity. The manufacturing process is labor-intensive, technically demanding, and expensive, limiting broad accessibility. Metabolic reprogramming offers one route forward: studies show that overexpressing PGC-1alpha, a master regulator of mitochondrial biogenesis, restores metabolic fitness and expansion capacity in exhausted TILs, enhancing memory CD8-positive T cell formation and antitumor activity. Such interventions represent a growing toolkit for rejuvenating cells that would otherwise fade before finishing the job.

CAR-T therapy, by contrast, takes a fully engineered approach. T cells are modified to express a chimeric receptor combining an antibody-derived antigen-binding fragment with T cell signaling domains, allowing them to kill tumor cells independently of MHC presentation, thereby sidestepping a common immune-evasion trick. The technology has advanced through five generations, from a simple receptor coupled to CD3ζ signaling, through designs incorporating CD28 or 4-1BB costimulatory domains, to fourth-generation cells that secrete cytokines such as IL-12 or IL-15 to remodel the tumor microenvironment, and fifth-generation platforms that integrate CRISPR-Cas9 editing for scalable manufacturing. CAR-T has delivered dramatic results in blood cancers since tisagenlecleucel’s 2017 approval, but melanoma has proven far harder. The only published clinical trial, targeting VEGFR2 in twenty-four melanoma patients, produced no objective responses and was terminated early. Preclinical work continues against targets including GD2, c-Met, CD70, gp100, and NY-ESO-1, with one Phase I study testing vaccine-primed CAR-T cells to promote in vivo expansion in relapsed melanoma.

TCR-T therapy occupies a middle ground, engineering peripheral blood T cells to express receptors with known specificity for tumor antigens presented on MHC molecules, granting access to intracellular targets that antibodies cannot reach. Melanoma supplied the field’s founding antigens, MART-1 and gp100, and early trials showed promise: a 2006 study achieved remission in two of thirteen metastatic melanoma patients, while later work with high-affinity MART-1 receptors reached a thirty percent response rate and NY-ESO-1-targeted cells achieved forty-five percent in metastatic melanoma. The approach has since earned its first approval in synovial sarcoma with afamitresgene autoleucel, and TCR-T cells targeting the HPV oncoprotein E7 have shown fifty percent response rates in virus-driven cancers. Key limitations persist, however, including MHC restriction, tumor downregulation of MHC expression, off-tumor toxicity in normal tissues, and the difficulty of identifying receptors with ideal specificity and affinity.

The review’s forward-looking section maps five optimization frontiers. Enriching tumor-reactive T cells, whether through peptide-MHC multimer sorting, neoantigen-guided expansion informed by whole-exome and RNA sequencing, or selection of activation markers such as CD137, promises to strip away useless bystander cells and concentrate therapeutic firepower. Multi-target CAR designs, such as tandem receptors against CD70 and B7-H3, counter antigen escape, while bispecific chimeric TCRs and HLA-agnostic screening platforms bypass MHC restrictions. To improve infiltration and persistence, engineers are arming cells with chemokine receptors like CXCR2 to home in on CXCL1-producing melanoma cells, expressing heparanase to digest the dense extracellular matrix, knocking out PD-1 or AKT genes via CRISPR, and deploying armored CARs that secrete IL-12 or IL-18 to recruit supportive macrophages and suppress regulatory T cells. Safety innovations, including inducible caspase-9 suicide switches and controllable CAR platforms, aim to tame cytokine release syndrome and neurotoxicity.

Combination strategies may ultimately prove decisive. Oncolytic viruses delivered systemically can inflame tumors and dual-activate CAR-T cells through both engineered and natural antigen recognition, significantly prolonging survival in mouse models. Photothermal therapy using PLGA-ICG nanoparticles disrupts tumor stroma and boosts T cell infiltration, while pairing TIL therapy with PD-1 inhibitors or PD-1-knockout melanoma-specific T cells with alpha-particle-conjugated PD-L1 blockers has produced synergistic effects in preclinical studies. The authors conclude that while tumor heterogeneity, immunosuppressive microenvironments, manufacturing complexity, and toxicity remain formidable barriers, advances in genetic engineering, single-cell sequencing, and artificial intelligence-driven antigen discovery are converging to address them. If cost-effective manufacturing and validated combinations follow, adoptive cell therapy could evolve from a specialized achievement into a cornerstone of melanoma treatment and, eventually, of solid tumor medicine more broadly.

Subject of Research: Adoptive cell therapy strategies, including TIL, CAR-T, and TCR-T approaches, for treating advanced melanoma

Article Title: Application and Advances of Adoptive Cell Therapy for Melanoma

Article References: Wei, C., Xie, L., Wei, C., & Gu, J. (2025). Application and Advances of Adoptive Cell Therapy for Melanoma. Clinical Cancer Bulletin, 4(1), Article 17. https://doi.org/10.1007/s44272-025-00045-z

Image Credits: AI Generated

DOI: 10.1007/s44272-025-00045-z

Keywords: melanoma, adoptive cell therapy, TIL therapy, CAR-T, TCR-T, lifileucel, immunotherapy, tumor microenvironment, CRISPR, immune checkpoint inhibitors, oncolytic viruses, cancer immunotherapy