Inhibition of KDEL receptors remodels the tumor microenvironment for robust T cell independent tumor regression

Tumor immunotherapy is supported by low-grade inflammatory conditions at the microenvironment, triggered by immunogenic cell death (ICD). However, ICD is dampened when tumors acquire resistance, affecting immune recognition. KDEL receptors (KDELRs), through a retrograde Golgi-to-ER transport, prevent spontaneous secretion of KDEL proteins. We report that inhibition of a single KDELR in a minor fraction of tumor cells, primarily KDELR2, provokes robust infiltration of macrophages and neutrophils into the tumor microenvironment, resulting in a complete regression of both immunogenic and non-immunogenic tumors independently of T cells. Importantly, in the course of regression, anti-tumor T cells are primed, conferring protection against a second challenge. Recapitulated by intratumoral delivery of siDKELR2 utilizing lipid nanoparticles, we implicate KDELR2 as a target to unleash an unusual robust innate immune response, which represents a tractable approach to initiate an adaptive response downstream, bypassing conventional ICD-inducing therapies. We propose KDELR targeting as a strategy to improve immunotherapy across tumor types, including “cold” tumors resistant to T cell-based immunotherapies.