PD-1–targeted cis-delivery of an IL-2 variant induces a multifaceted antitumoral T cell response in human lung cancer

Antibody-cytokine fusion proteins are being developed as next-generation cancer immunotherapies, aiming to deliver activation signals to targeted immune populations. Among these, PD1-IL2v-an engineered interleukin-2 variant (IL-2v) lacking CD25 binding, fused to a high-affinity programmed cell death protein 1 (PD-1) blocking antibody-has shown promising results in murine tumor models. Here, using human model systems, we show that PD1-IL2v elicits a multifaceted antitumor T cell response by targeting both CD8+ and conventional CD4+ T (Tconv) cells. Single-cell RNA sequencing (scRNAseq) on a lung cancer patient-derived tumor fragment (PDTF) platform revealed that PD1-IL2v drives the expansion of proliferative, cytotoxic CD8+ T cells exhibiting features of tumor reactivity. This was accompanied by up-regulation of CXCR6, enhancing their migratory capacity. In Tconv cells, PD1-IL2v up-regulated CXCL13 expression and promoted a T follicular helper/T helper 1 (TFH/TH1)-like transcriptional program associated with anti-PD1 responsiveness. Our findings provide mechanistic insights into the effects of IL-2v-targeted delivery to PD-1+ cells within human tumors, supporting the clinical development of next-generation immunocytokines.