PolarTIL programming reveals an essential role for TGF-β1 in antitumor memory in human cutaneous malignancies

Abstract Tumor-infiltrating lymphocyte (TIL) therapy can induce tumor regression in solid malignancies, yet durable responses remain limited, highlighting the need for more effective cell products. Here, we generated a novel TIL product, PolarTIL, by polarizing murine and human TIL from cutaneous malignancies ex vivo with a defined Type-17 cytokine cocktail. Compared with conventional IL-2 culture, PolarTIL produced greater cell yields and a distinct cellular state marked by reduced CD4⁺ regulatory T cells, enrichment of CD103⁺ populations, and superior antitumor activity in vitro and in vivo . Unexpectedly, TGF-β1 emerged as a critical regulator of PolarTIL function. Although TGF-β is commonly targeted for inhibition in cancer immunotherapy, its removal during PolarTIL generation completely abolished therapeutic efficacy in vivo . Together, these findings reveal an unrecognized requirement for TGF-β1 in programming effective TIL responses and establish PolarTIL as a promising next-generation cellular therapy for solid tumors.