Tailored Biomaterials Induce Tertiary Lymphoid Structures for Boosting Cancer Immunotherapy

A central obstacle in cancer immunotherapy is the "cold" tumor, characterized by limited immune infiltration, which renders it largely unresponsive to treatment. Tertiary lymphoid structures (TLS), functioning as ectopic immune niches, can convert these cold tumors into "hot" ones by supporting antigen presentation, lymphocyte activation, and coordinated immune responses. Therefore, strategies to induce TLS formation hold significant therapeutic promise. Recent studies have explored a range of biomaterial systems designed to orchestrate the formation of TLS within the tumor microenvironment. This encompasses synthetic biomaterial platforms (nanocarriers, stimulus-responsive hydrogels, programmable 3D scaffolds, and mesoporous materials), natural and bioderived systems (organoids and exosomes), as well as emerging bioactive entities (engineered immune cells, oncolytic viruses, and bacteria). This review outlines the cellular composition, maturation process, and immunological functions of TLS, highlights diverse biomaterial platforms facilitating TLS formation, and summarizes translational challenges, including biosafety, standardization, and scalability. Inducible TLS (iTLS) provide a potent means to remodel the tumor immune microenvironment, offering exciting opportunities for advanced cancer immunotherapy.