IMMSTRESS · Targeting stress signaling pathways to enhance prostate cancer immunotherapy

Prostate cancer (PCa) is the most common cancer in men and a leading cause of cancer-related death. Its poor response to current immunotherapies highlights the urgent need for new strategies. Six-Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) is a cell-surface antigen overexpressed in most primary and advanced stage PCa, making it a highly attractive immunotherapy target. However, the highly suppressive tumor microenvironment (TME) in PCa strongly limits immunotherapy effectiveness. One of the key drivers of this immunosuppression is the persistent activation of endoplasmic reticulum stress pathways, particularly the inositol-requiring protein 1α (IRE1α) and PKR-like ER kinase (PERK) branches of the unfolded protein response (UPR), which enable tumor cells to survive and evade immune attack. Combining STEAP1-targeted immunotherapies with selective UPR inhibition therefore holds strong potential to overcome these barriers. Due to its transient yet versatile nature, messenger RNA (mRNA) technology enables precise and dynamic modulation of the TME while potently activating anti-tumor immune responses. In this project, we will leverage mRNA platforms to deliver STEAP1-targeted immunotherapies together with UPR inhibition to reprogram the TME for more durable tumor control. Specifically, we will test whether inhibiting IRE1α or PERK can reprogram the PCa TME and unlock the full potential of STEAP1-targeted treatments. By integrating mRNA-based delivery with UPR blockade, we aim to both redirect and amplify anti-tumor T-cell activity while enhancing their persistence in the hostile TME. This approach combines antigen-specific targeting with dynamic immune modulation to overcome immune evasion, achieve durable tumor control, and establish a broadly applicable strategy for solid tumors beyond PCa.