Follicular T cell subsets and tertiary lymphoid structures may guide immunotherapy in ovarian cancer

Photo by Steve A Johnson / Unsplash

Frontiers in Medicine Published June 2, 2026 Medically reviewed June 2, 2026 DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider follicular T cell and tertiary lymphoid structure features as potential biomarkers in ovarian cancer immunotherapy.

This is a narrative review that synthesizes current evidence on immune features in ovarian cancer, particularly high-grade serous ovarian cancer. The authors discuss follicular T cell subsets (Tfh, Tfr, Tfc), tertiary lymphoid structures, immune checkpoint inhibitors, chemokine axis targeting, metabolic interventions, and engineered cell-based therapies, comparing them to conventional CD8+ T cell–centric models.

The review argues that follicular immune features and tertiary lymphoid structures represent promising therapeutic avenues to overcome immunotherapy resistance. It highlights these features as potential biomarkers for predicting immunotherapy response and for patient stratification.

The authors acknowledge gaps and limitations in the current evidence, noting that the field is still developing. They do not report specific study populations, intervention details, or safety data.

Practice relevance is restrained: the review identifies potential directions for future research and clinical investigation rather than providing definitive treatment recommendations. Clinicians should interpret these findings as hypothesis-generating.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedJun 2026

View Original Abstract ↓

BackgroundOvarian 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.Main bodyFollicular 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.ConclusionsCollectively, 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.