A New Strategy for Controlled In Situ Release of IL‐2 from Tumor Spheroids Using a NIR‐II Light‐Mediated Optogenetic Manipulation System

Interleukin-2 (IL-2) is a clinically significant immunotherapeutic agent; its short half-life and poor targeting specificity in vivo have made controlled in situ release an important area of investigation. However, traditional 2D cell experiments and animal studies cannot fully replicate the real environment of human tumors and are limited by interspecies heterogeneity. Here, a NIR-II light-mediated optogenetic manipulation system based on photothermal conjugated polymer nanoparticles is successfully constructed, enabling the controlled in situ release of IL-2 from 3D tumor spheroids. Maintaining tumor spheroids at a relatively low temperature (≈40 °C) can enhance IL-2 release by up to 4.3 times upon irradiation with 1080 nm laser for 30 min. The released IL-2 further activates peripheral NK-92 cells, enhancing the efficacy of immunotherapy. Additionally, the in situ release of IL-2 specifically upregulates the expression of IL-2RA on NK-92 cells, facilitating the formation of high-affinity complexes between IL-2 and IL-2RA. This process activates multiple signaling pathways, including JAK-STAT, PI3K-Akt, and MAPK, for improved immunotherapy. Therefore, this NIR-II light-mediated optogenetic system provides a promising method for the controlled in situ release of important cytokines in the 3D tumor immune microenvironment for immunotherapy.