Engineering nanomedicines to reshape tertiary lymphoid structures: A new perspective on antitumor immunotherapy

Tertiary lymphoid structures (TLS), which form as tumor-localized lymphoid-like structures, play a critical role in enhancing immune responses and improving prognosis. However, native TLS is highly prone to developmental arrest within the tumor microenvironment (TME), and conventional free-circulating drugs suffer from significant drawbacks such as short half-lives and high systemic toxicity. Nanomedicines, with their advantages of spatiotemporally controlled release, deep physical penetration, and multi-target co-delivery, offer an engineered solution for reshaping the TME and inducing TLS formation. This article systematically summarizes engineered intervention strategies for nanomedicine-induced TLS formation across three key aspects: activating chemotactic networks to accelerate immune cell homing; targeting matrix reprogramming to induce high-endothelial microvessels for physical scaffold construction; and enhancing antigen cross-presentation to drive germinal center (GC) maturation. Furthermore, the paper explores in depth how nanomedicine-mediated TLS functions as an immunological hub, generating synergistic effects with existing immune checkpoint inhibitors, cellular therapies, and physical therapies. Finally, it analyzes the current barriers to clinical translation in this field and outlines a blueprint for future development. Through a multidisciplinary perspective, this paper provides theoretical guidance and a technical roadmap for the design and clinical application of next-generation precision immunotherapy nanomedicines.