Targeting Endoplasmic Reticulum Stress to Overcome Immunosuppression and Enhance Immunotherapy in Ovarian Cancer
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| Year of publication | 2026 |
| Type | Appeared in Conference without Proceedings |
| Citation | |
| Description | Ovarian Cancer (OC) remains one of the most lethal gynecological malignancies, characterized by late-stage diagnosis and a high rate of recurrence. While immunotherapy has transformed the treatment landscape for many cancers, its efficacy in OC has been hindered by a hostile Tumor Immune Microenvironment (TIME; Emmanuelli et al., 2024). This study explores the pivotal role of Endoplasmic Reticulum Stress (ERS) modulation in reshaping the TIME of OC. By utilizing in vitro models and a syngeneic in vivo murine model, we evaluated how ERS modulation can influence tumor progression and immune response. We identified the impact and potential of ERS modulation in cancer–immune co-cultures. We characterized the expression of key ERS-related genes and their translational level and spatial localization. These findings were applied to model the effects of dendritic cell vaccine immunotherapy in OC in vivo. In an OC murine model, the combination of ERS modulation and a Dendritic Cell Vaccine (DCV) achieved the greatest reduction in tumor burden, decreasing both tumor volume and weight by 40%. This synergy was characterized by a shift in the immune profile: a reduction in immunosuppressive markers in the spleen and an increase in pro-apoptotic signaling and CD3+ T-cell infiltration within the tumor tissue. Our results demonstrate that ERS modulation reconfigures the TIME to enhance the antitumor activity of immune cells, thereby improving immunotherapy efficacy. By attenuating systemic immunosuppression, ERS-targeted therapies could overcome the "cold" immune nature of many cancers. This study provides a strong mechanistic rationale for combining ERS modulators with immunotherapy to enhance therapeutic outcomes in resistant OC phenotypes. |