Taxane chemotherapy promotes response to TIM-3 checkpoint blockade via STING-mediated ER stress and HMGB1 secretion.

Immune checkpoint inhibitors are increasingly being used in conjunction with chemotherapy regimens, but the reasons for the success or failure of these combinations remains unclear. In previous studies, we described how blocking TIM-3 promotes activation of dendritic cells through HMGB1-dependent DNA uptake, resulting in efficacy when combined with paclitaxel. Here, we show that the release of HMGB1 by tumor cells is required for the combinatorial efficacy with TIM-3 blockade observed with paclitaxel, docetaxel, fluorouracil, and irradiation. HMGB1 release during taxane therapy is an active process involving nuclear export following Toll-like receptor 4 (TLR4)-dependent reactive oxygen species production, DNA damage, and poly(ADP-ribose) polymerase activation. DNA damage promotes the accumulation of cytosolic double-stranded DNA (dsDNA), which activates the cGAS-STING pathway; however, taxanes fail to induce type I interferons. Instead, STING activation promotes endoplasmic reticulum (ER) stress and lysosomal exocytosis, driving HMGB1 secretion. Thus, non-canonical STING signaling in response to taxanes can promote the efficacy of chemoimmunotherapy.