Unveiling the Role of JAK2/STAT3 Signaling in Chemoresistance of Gynecological Cancers: From Mechanisms to Therapeutic Implications.

Abstract

Gynecological cancers, encompassing ovarian, cervical, endometrial, vulvar, and vaginal cancers, present a significant global health burden due to high incidence rates and associated mortality. Among these, ovarian, cervical, and endometrial cancers are particularly challenging, characterized by late-stage diagnoses, distinct pathological features, and significant resistance to chemotherapy. A major contributor to treatment failure is chemoresistance, driven by multifactorial mechanisms such as dysregulation of apoptosis, DNA repair, metabolic reprogramming, and the tumor microenvironment. The Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a pivotal role in promoting chemoresistance, enhancing tumor cell survival, stemness, and immune evasion through the transcriptional regulation of anti-apoptotic and multidrug resistance genes. Persistent activation of this pathway not only sustains tumor progression but also limits the efficacy of standard chemotherapeutics, such as paclitaxel, cisplatin, and platinum-based agents. This review comprehensively examines the molecular mechanisms underlying JAK2/STAT3-mediated chemoresistance in gynecological cancers, highlighting its interactions with critical regulatory networks, including non-coding RNAs, cytokine signaling, hypoxia, and extracellular vesicles. We further explore therapeutic interventions targeting the JAK2/STAT3 axis, encompassing small molecule inhibitors, monoclonal antibodies, nanoparticles, and oncolytic viruses. Natural products and synthetic compounds targeting this pathway demonstrate significant potential in overcoming resistance and improving chemotherapy response. The findings underscore the critical role of JAK2/STAT3 signaling in the persistence and progression of chemoresistant gynecological cancers and advocate for the integration of pathway-targeted therapies into current treatment paradigms. By disrupting this axis, emerging therapies offer a promising strategy to enhance drug sensitivity and improve patient outcomes, paving the way for more effective and personalized approaches in gynecological oncology.