Inhibition of KDEL Receptors Remodels the Tumor Microenvironment for T Cell Independent Tumor Regression

ABSTRACT Tumor immunotherapy is supported by low‐grade inflammatory conditions in 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 regression of both immunogenic and non‐immunogenic tumors initially 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.