Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance

Simple Summary Prostate cancer remains a significant health issue, particularly when it progresses to castration-resistant (CRPC) and metastatic CRPC (mCRPC). This review explores the role of interleukin-8 (IL-8) and its receptors, CXCR1 and CXCR2, in prostate cancer. IL-8 remains a key player in inflammation and tumour growth, promoting cancer cell survival, migration, and resistance to therapies. By targeting IL-8 signalling, researchers aim to develop new treatments that can enhance the effectiveness of existing therapies and improve outcomes for patients with resistant forms of prostate cancer. This approach could lead to better management of the disease and provide new hope for patients facing limited treatment options.Abstract This review delves into the intricate roles of interleukin-8 (IL-8) and its receptors, CXCR1 and CXCR2, in prostate cancer (PCa), particularly in castration-resistant (CRPC) and metastatic CRPC (mCRPC). This review emphasizes the crucial role of the tumour microenvironment (TME) and inflammatory cytokines in promoting tumour progression and response to tumour cell targeting agents. IL-8, acting through C-X-C chemokine receptor type 1 (CXCR1) and type 2 (CXCR2), modulates multiple signalling pathways, enhancing the angiogenesis, proliferation, and migration of cancer cells. This review highlights the shift in PCa research focus from solely tumour cells to the non-cancer-cell components, including vascular endothelial cells, the extracellular matrix, immune cells, and the dynamic interactions within the TME. The immunosuppressive nature of the PCa TME significantly influences tumour progression and resistance to emerging therapies. Current treatment modalities, including androgen deprivation therapy and chemotherapeutics, encounter persistent resistance and are complicated by prostate cancer's notably "immune-cold" nature, which limits immune system response to the tumour. These challenges underscore the critical need for novel approaches that both overcome resistance and enhance immune engagement within the TME. The therapeutic potential of inhibiting IL-8 signalling is explored, with studies showing enhanced sensitivity of PCa cells to treatments, including radiation and androgen receptor inhibitors. Clinical trials, such as the ACE trial, demonstrate the efficacy of combining CXCR2 inhibitors with existing treatments, offering significant benefits, especially for patients with resistant PCa. This review also addresses the challenges in targeting cytokines and chemokines, noting the complexity of the TME and the need for precision in therapeutic targeting to avoid side effects and optimize outcomes.