Targeting store-operated Ca2+ entry as a novel strategy to overcome treatment resistance in melanoma.

Cutaneous melanoma is the most aggressive form of skin cancer characterized by high metastatic potential and poor prognosis, particularly in advanced stages (stage III/IV). Despite more than a decade of significant advances in treatment including immunotherapies, oncolytic virus therapy, and adoptive cell therapy, clinical outcomes for patients with advanced melanoma remain unsatisfactory. This is primarily due to the tumor's intrinsic aggressiveness, intolerable side effects associated with treatments, and the rapid emergence of therapeutic resistance. Therefore, there is a critical need for novel therapeutic strategies that not only inhibit melanoma progression and metastasis but also overcome resistance mechanisms. After reviewing recent therapeutic developments, we highlight the potential of store-operated Ca2+ entry (SOCE) as a promising and thus far overlooked target to improve the efficacy of current melanoma therapies. We examine the role of SOCE in oncogenic signaling pathways driving melanoma progression and invasiveness. Emphasis is given to the key mechanisms regulated by SOCE that underlie therapeutic resistance. We further discuss how modulation of SOCE has the potential to reshape a tumor response to therapy by disrupting these mechanisms. Integrating SOCE modulation in combination with existing treatment paradigms holds significant potential for advancing more precise, durable, and patient-tailored interventions in advanced melanoma.