Follicular T cells in the ovarian cancer immune microenvironment: biological insights and translational implications

Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), exhibits a generally poor response to immune checkpoint inhibitors, and its underlying mechanisms remain incompletely defined. This observation suggests that an immunological framework focused predominantly on CD8⁺ cytotoxic T cells is insufficient to fully explain immune resistance in ovarian cancer. Increasing evidence highlights the importance of tertiary lymphoid structures (TLS) and follicular immune responses in coordinating antitumor immunity and shaping therapeutic outcomes.

Follicular T cell subsets-including follicular helper T cells (Tfh), follicular regulatory T cells (Tfr), and CXCR5⁺ follicular-like cytotoxic CD8⁺ T cells (Tfc)-form a dynamic immunoregulatory axis that governs B-cell activation, germinal center-like structure formation, antigen presentation, and local immune microenvironment remodeling. In this review, we systematically summarize the differentiation programs and regulatory mechanisms of follicular T cells and their compartment-specific distribution and functional remodeling in ovarian cancer. We integrate current evidence regarding their interactions with TLS maturation, B-cell function, and effector CD8⁺ T cell responses. Attention is given to the emerging concept that dysregulation of the follicular T cell axis-especially an elevated Tfr/Tfh ratio and defective functional maturation of TLS-may contribute to immune suppression and resistance to immunotherapy in ovarian cancer. From a translational perspective, we discuss therapeutic strategies aimed at reprogramming follicular T cell responses, including immune checkpoint modulation, chemokine axis targeting, metabolic interventions, and engineered cell-based therapies. We also highlight follicular immune features as potential biomarkers for immunotherapy response prediction and patient stratification.

Collectively, this review proposes a follicular T cell-centered immunological framework that extends beyond conventional CD8⁺ T cell-centric models and identifies promising therapeutic avenues to overcome immunotherapy resistance in ovarian cancer.