Non-immune stromal, vascular, and matrix components play coordinated and necessary roles in TLS formation

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, spanning 3 journals. Those papers have been cited 1 times in total.

Supporting evidence — 3 representative gaps

• Adjacent nontumor mucosa: The overlooked frontier in colorectal cancer prognostication (2026) · World Journal of Gastroenterology · doi

  The author(s) declare that no financial support was received for the research and/or publication of this article. therapeutic response. Within CRC is a biologically heterogeneous malignancy in which the TME plays a pivotal role in shaping disease progression, immune dynamics, and the CRC immune landscape, diverse innate and adaptive immune cells—including CTLs, natural killer NK cells, DC, Tregs, TAMs, and MDSCs—orchestrate a balance between anti-tumoral immunity and immune escape (Ferkel et al., 2025). This balance is heavily influenced by molecular subtypes of CRC, particularly MSI-H versus MSS tumors, and further modulated by the stromal architecture, ECM, and gut microbiota (Gopalakrishnan et al., 2018). Robust evidence supports the prognostic and therapeutic significance of tumor-infiltrating lymphocytes (TILs), especially CD8+ T cells, with high infiltration correlating with improved outcomes and response to ICIs in MSI-H CRC (Pagès et al., 2018). This has positioned ICIs as a standard of care in this subset. However, the immunologically “cold” nature of most MSS CRCs, characterized immunosuppressive cell by low TIL density and enriched

  generalfuture work
  Keywords: immune cells therapeutic response balance icis author declare financial support received publication article within biologically
• Radiotherapy and tertiary lymphoid structures: balancing immune activation and immune damage in cancer immunotherapy (2026) · Molecular Cancer · cited 1× · doi

  While the RT-TLS relationship provides a framework for assessing local therapy beyond tumor-cell killing, the field remains at an early stage of validation. RT can alter antigen release, innate immune signaling, lymphocyte trafficking, vascular states, and lymph-node function. TLSs are clinically relevant immune-organizing niches, yet it remains unresolved whether RT can deliberately preserve or generate functional TLSs. The evidence reviewed here supports a state-, dose-, space- and time-dependent model. The strongest evidence concerns RT-induced ICD, cGAS-STING/type I interferon signaling, lymphocyte depletion, and TDLN effects. Direct TLS-specific evidence is more limited and context-dependent, including selected models of low- dose RT-associated TLS-like organization and clinical tissue studies showing disruption of mature TLSs after certain treatment regimens. Several technical bottlenecks need to be addressed before TLS-guided RT can be translated. Current TLS assessment still relies mainly on tissue-based pathology, multiplex immunofluorescence and spatial profiling, which are invasive, sampling- dependent and difficult to repeat dynamically. TLS scoring is not yet standardized across tumor types, and noninvasive methods such as radiomics or circulating biomarkers require external validation against spatial histology. Practical countermeasures include harmonized TLS scoring criteria, paired pre- and post-treatment biopsies when feasible, integration of tumor tissue, TDLNs, peripheral blood and imaging data and prespecified TLS endpoints in RT- immunotherapy trials. These endpoints should distinguish TLS density from maturity, germinal-center activity, HEV/FDC/FRC integrity, spatial localization, and suppressive stromal or myeloid barriers. ARTICLE IN PRESSARTICLE IN PRESS ACCEPTED MANUSCRIPT Future trials should therefore treat TLSs first as stratification biomarkers and exploratory endpoints. Paired assessments of TLS density and maturity, HEV and FDC/FRC integrity, DLN function, TCR/BCR repertoires, circulating CXCL13 and imaging or digital pathology predictors are needed to distinguish functional immune organization from transient inflammation. Contemporary RT-immunotherapy studies in nasopharyngeal carcinoma, esophageal adenocarcinoma, cisplatin-ineligible head and neck cancer, Merkel cell carcinoma, and cold NSCLC provide clinical design contexts for future RT-TLS trials [216–220]. Future RT-TLS protocols should explicitly add paired tissue, blood and, where feasible, nodal immune monitoring rather than assuming that these elements are already present across all template studies. Therapeutically, the near-term priority is to test stratified combinations without assuming that TLS biology is clinically controllable. RT may provide antigen release and innate immune activation; STING or LTβR agonists may amplify organogenesis- related signals in preclinical settings; ICB may relieve adaptive suppression; and vascular normalization or stromal reprogramming may improve lymphocyte access and residence. Overall, TLS-oriented RT remains a promising research hypothesis rather than an established clinical strategy. The central challenge is to determine whether RT can reproducibly preserve or promote functional mature TLSs, in which tumor types and under which RT–immunotherapy conditions, and whether such effects translate into durable clinical benefit.

  generalfuture work
  Keywords: immune tlss tumor clinical tissue remains lymphocyte whether functional evidence dependent spatial paired endpoints immunotherapy
• Non-immune regulation of tertiary lymphoid structures in cancer (2026) · Frontiers in Immunology · doi

  Non-immune stromal, vascular, and matrix components play coordinated and necessary roles in TLS formation. CAFs establish stromal networks and chemokine gradients that organize immune cells, either supporting or suppressing TLS formation. HEVs regulate lymphocyte access through specialized adhesion molecules, while the ECM provides the biochemical and biomechanical frame- work that supports TLS structure and function. Indeed, successful TLS formation depends on coordinated interactions between immune and non-immune components of the TME. Evolving spatial technologies will help to define the mechanisms through which the TME regulates TLS formation, characterize the trajectory of TLS maturation, and clarify the functional importance of TLS localization within the tumor. These advances may lead to the discovery of novel targets to improve ICI efficacy and cancer patient outcomes.

  generalfuture work
  Keywords: immune formation stromal components coordinated vascular matrix play necessary roles cafs establish networks chemokine gradients

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