Linear ubiquitination‐induced necrotic tumor remodeling elicits immune evasion

Abstract

Tumor‐elicited inflammation confers tumorigenic properties, including cell death resistance, proliferation, or immune evasion. To focus on inflammatory signaling in tumors, we investigated linear ubiquitination, which enhances the nuclear factor‐κB signaling pathway and prevents extrinsic programmed cell death under inflammatory environments. Here, we showed that linear ubiquitination was augmented especially in tumor cells around a necrotic core. Linear ubiquitination allowed melanomas to tolerate the hostile tumor microenvironment and to extend a necrosis‐containing morphology. Loss of linear ubiquitination resulted in few necrotic lesions and growth regression, further leading to repression of innate anti‐PD‐1 therapy resistance signatures in melanoma as well as activation of interferon responses and antigen presentation that promote immune‐mediated tumor eradication. Collectively, linear ubiquitination promotes tumor‐specific tissue remodeling and the ensuing immune evasion.