Tumour-infiltrating lymphocyte therapy comes of age in the era of genetic engineering

Advances in cancer immunotherapy from immune checkpoint modulation to adoptive cell transfer of tumour-infiltrating lymphocytes (TILs) have greatly improved outcomes for patients with advanced cancers, particularly metastatic melanoma. The approval of TIL therapy in 2024 following two independent landmark clinical trials has established this approach as a viable treatment option, with response rates of up to 50% in treatment-resistant melanoma. Genetic engineering offers new opportunities to further improve TIL efficacy and durability, including viral vector-mediated overexpression of cytokines or chimeric receptors, and non-viral genome editing techniques such as CRISPR-Cas9 to delete inhibitory genes such as PD-1 and CISH. In this Review we outline the current state of genetically engineered TILs, highlighting both preclinical advances and ongoing clinical trials. As these engineered products are evaluated in clinical settings, they are expected to expand the personalised immunotherapy toolkit and improve durable outcomes across a broader range of solid tumours.