A novel immunological perspective on female-specific cancers: Exploring the signaling pathways of tertiary lymphoid structures and their clinical applications

Female-specific cancers, including breast, cervical, and ovarian cancers, are significant contributors to global morbidity and mortality. Despite advancements in conventional treatment modalities, challenges such as recurrence and therapeutic resistance remain prevalent, highlighting the urgent need for novel therapeutic strategies. Tertiary lymphoid structures (TLS), which act as immune microstructures within the tumor microenvironment, have emerged as key regulators of antitumor immunity. Increasing attention has been directed toward understanding their presence and functional roles in gynecological malignancies. Effective assessment and quantification of TLS can aid in evaluating clinical outcomes for patients with gynecological cancers. Current research has focused on the mechanisms driving TLS formation, techniques for their assessment, and therapeutic strategies aimed at promoting their development. This review comprehensively examines the distribution, structural characteristics, and functional roles of TLS in female-specific cancers, emphasizing their ability to activate localized immune responses through signaling pathways such as NF-κB, STAT3, and Wnt. These pathways play key roles in regulating TLS formation, immune cell infiltration, and the modulation of antitumor immunity. This is the first review to systematically explore the interaction between TLS and hormone signaling, particularly estrogen and progesterone, within tumor microenvironments of breast and ovarian cancers. Furthermore, the clinical potential of TLS is explored, highlighting its use as a biomarker for predicting therapeutic efficacy and disease prognosis and its role in guiding novel immunotherapeutic strategies. By systematically analyzing the signaling pathways and immune regulatory mechanisms associated with TLS, this review provides a strong scientific foundation for the development of innovative immunotherapies targeting gynecological cancers.