Non-immune regulation of tertiary lymphoid structures in cancer

Tertiary lymphoid structures (TLS) are ectopic immune aggregates that form in response to chronic inflammation, and their presence across many solid tumors has been associated with improved survival and enhanced responses to immunotherapy. Although current models primarily characterize TLS through the lens of immune aggregation and organization, their formation also depends on reciprocal interactions with the non-immune tumor microenvironment. Fibroblasts, vasculature, extracellular matrix architecture, and tumor metabolism collectively influence TLS development, suggesting that these structures function as emergent tissue ecosystems rather than as immune aggregates alone. In this review, we summarize current evidence on how cancer-associated fibroblasts and the tumor vasculature regulate immune cell recruitment and organization through context-dependent expression of chemokines, adhesion molecules, structural barriers, and vascular niches, before considering how extracellular matrix remodeling and tumor metabolism further shape TLS neogenesis and maturation. Across these processes, non-immune components exhibit dual functions, promoting TLS formation in some contexts while reinforcing immune exclusion and antagonizing TLS in others. We further discuss current spatial technologies that enable in-depth quantification of TLS structure and maturity and clarify the contribution of non-immune components to TLS biology. Due to this increased appreciation of their biological relevance, we discuss the promise of non-immune components as rational targets for combination strategies to enhance TLS function and immunotherapy efficacy.