IL-18 from microwave-ablated osteosarcoma drives antitumor immunity, synergizing with anti-PD-1 therapy.

Despite standard treatments, survival rates for osteosarcoma (OSA), the most common primary malignant bone tumor in children and adolescents, have not improved significantly. Microwave ablation (MWA) is an emerging thermal therapy that induces antitumor immunity, but its intrinsic mechanisms remain elusive. This study investigates how MWA promotes interleukin-18 (IL-18) expression and enhances dendritic cell (DC) functions, leading to CD8+ T cell infiltration, addressing a critical gap in understanding MWA's immunomodulatory effects.

In vitro, MWA-treated OSA cells were co-cultured with bone marrow dendritic cells (BMDCs) to assess their activation, antigen uptake, and cross-presentation. RNA-sequencing was performed to analyze the intrinsic mechanisms of BMDCs stimulated by MWA-treated OSA. In vivo, a mouse model of primary osteosarcoma of the femur was established to evaluate immune responses and measure the additive tumor eradication effects of IL-18 cytokine and anti-programmed cell death protein 1 (PD-1) combination therapy.

MWA significantly promoted the activation, antigen uptake, and antigen cross-presentation of BMDCs. Mouse models demonstrated that MWA treatment elevated the proportion of CD8+ T cells and CD11c+ DCs both in tumors and draining lymph nodes. The tumor suppression was mediated through the release of IL-18 by MWA-treated OSA and its interaction with the IL-18 receptor on DCs, a mechanism that was reversed after anti-IL-18 antibodies application. Furthermore, IL-18 cytokine alone exerted a tumor eradication effect.

IL-18 cytokine showed an additive role against OSA when combined with anti-PD-1 therapy, highlighting a potent synergistic therapeutic strategy.