Immunogenic cell death and tertiary lymphoid structures: bridging tumour cell death and immune organization

Recent studies suggest that the formation of tertiary lymphoid structures (TLSs) could be associated with better survival from certain cancers. In this Perspective, we propose that immunogenic cell death (ICD) can act as an upstream organizer of tumour-associated TLSs by coordinating vascular, stromal and immune reprogramming in the tumour microenvironment. ICD leads to the release of tumour antigens and damage-associated molecular patterns that activate innate pathways, such as cGAS-STING signalling, in dendritic cells, myeloid cells, endothelial cells and stromal fibroblasts. These activated cells release type I interferons, TNF and chemokines, such as CCL19, CCL21 and CXCL13, that promote endothelial cell activation and the differentiation of high endothelial venule-like structures. This enables the recruitment of naive and memory lymphocytes and the emergence of perivascular T cell-dendritic cell aggregates, which can form the basis of TLSs. Full structural maturation of TLSs, with segregated B cell and T cell zones, follicular dendritic cell networks and germinal centres, appears to require additional lymphotoxin β receptor (LTβR)-dependent stromal reprogramming. Together, this suggests a two-step model in which ICD first seeds inflammatory vascular niches and then, through LTβR-mediated tissue organization, supports the development of functional TLSs.