Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response

Abstract

Despite advances in cancer therapy, several persistent issues remain. These include cancer recurrence, effective targeting of aggressive or therapy-resistant cancers, and selective treatments for transformed cells. This review evaluates the current findings and highlights the potential of targeting the unfolded protein response to treat cancer. The unfolded protein response, an evolutionarily conserved pathway in all eukaryotes, is initiated in response to misfolded proteins accumulating within the lumen of the endoplasmic reticulum. This pathway is initially cytoprotective, allowing cells to survive stressful events; however, prolonged activation of the unfolded protein response also activates apoptotic responses. This balance is key in successful mammalian immune response and inducing cell death in malignant cells. We discuss how the unfolded protein response affects cancer progression, survival, and immune response to cancer cells. The literature shows that targeting the unfolded protein response as a monotherapy or in combination with chemotherapy or immunotherapies increases the efficacy of these drugs; however, systemic unfolded protein response targeting may yield deleterious effects on immune cell function and should be taken into consideration. The material in this review shows the promise of both approaches, each of which merits further research.

Keywords

• unfolded protein response
• inositol-requiring enzyme 1 (ire1)
• pkr-like endoplasmic reticulum kinase (perk)
• glucose-regulated protein 78 (grp78)
• activating transcription factor 6 (atf6)
• immune cells
• t cell
• macrophage
• tumor microenvironment