In-depth insight into tumor-infiltrating stromal cells linked to tertiary lymphoid structures and their prospective function in cancer immunotherapy

Abstract Background and purpose The tumor microenvironment (TME) is widely acknowledged as a pivotal regulator of cancer progression. However, the dualistic role of tertiary lymphoid structures (TLSs), which serve as critical immune hubs within the TME, remains incompletely characterized, particularly with respect to their context-dependent capacity to either inhibit or facilitate tumor development. This review aims to synthesize current understanding of the complex interactions between stromal cells and TLSs, addressing existing gaps in mechanistic insight and exploring therapeutic avenues to exploit TLS plasticity. Key reviewed topics The current study critically reviews the mechanisms by which stromal components, including cancer-associated fibroblasts and endothelial cells, contribute to TLS neogenesis through chemokine-mediated recruitment of lymphocytes. Furthermore, it highlights the dual functional roles of TLSs as sites of both anti-tumor immune activation and immunosuppression, notably via the enrichment of regulatory T cells. The clinical implications of mature TLS presence, particularly their association with improved patient prognosis and enhanced therapeutic responsiveness, are also analyzed. Main conclusions TLSs demonstrate a bifunctional nature, wherein their spatial organization and dynamic interactions with stromal elements dictate the balance between immune activation and tolerance within the TME. While mature TLSs are generally correlated with favorable clinical outcomes, their potential to foster immunosuppressive microenvironments necessitates the development of precision-targeted interventions. The interplay between stromal cells and TLSs represents a promising therapeutic axis for modulating the tumor immune milieu. Future perspectives Future research should prioritize strategies aimed at promoting TLS maturation, disrupting immunosuppressive niches, and integrating TLS-modulating agents with existing immunotherapeutic regimens to enhance clinical efficacy. Additionally, the identification of robust biomarkers reflective of TLS functional states and the rigorous validation of stromal-targeted therapies within combinatorial treatment frameworks are imperative for advancing translational applications. Graphical abstract