Non-immune stromal, vascular, and matrix components play

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

• 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
• Advances in Radiotherapy for Soft Tissue Sarcomas in 2025: A Review (2026) · Current Oncology Reports · doi

  ● Integration of Biomarkers for Personalized RT: The future lies in moving beyond a one-size-fits-all ap- proach. The integration of histotype-specific response patterns [2], molecular profiles (e.g., CINSARC [42], PARP expression [25]), and real-time response data from mpMRI [23] or circulating tumor DNA will enable truly personalized RT prescriptions. Future trials must stratify patients using these biomarkers to test adaptive dose escalation, de-escalation, or specific combinatorial strategies. ● Next-Generation Systemic-RT Combinations and Sequencing: Building on early successes with PARPi and ICIs, research must optimize the sequencing, tim- ing, and dosing of these combinations. Furthermore, exploring novel agents (e.g., next-generation anti-an- giogenics, bispecific antibodies) and cellular therapies (CAR-T/NK cells) in combination with RT, guided by predictive biomarkers of synergy, represents a fertile frontier [12, 29]. ● AI-Enhanced Adaptive Radiotherapy and Quanti- tative Response Assessment: The fusion of artificial intelligence (AI) with adaptive RT platforms will be transformative. AI algorithms can automate the analy- sis of mpMRI and other imaging data to predict early response, enabling fully dynamic treatment adaptation [22]. Similarly, AI can aid in validating and standardiz- ing novel surrogate endpoints like hyalinization [28] or radiomic signatures, accelerating trial conduct. ● Validation of Surrogate Markers: Surrogate markers such as hyalinization [28], monocyte infiltration [41], and mpMRI parameters [23] need validation in large- scale prospective, multi-institutional trials to potentially replace traditional endpoints (e.g., OS, PFS) in clinical trials. This would accelerate the development of novel RT strategies by reducing trial duration and sample size requirements. ● Standardized QoL Measurement and Value-Based Care: Implementation of standardized QoL tools such as STS-QoL [43] in clinical practice and trials will enable Page 11 of 15 50 consistent monitoring of patient-reported outcomes. Fu- ture research should focus on identifying interventions to mitigate QoL declines during RT (e.g., supportive care, rehabilitation) and correlating QoL with long- term functional outcomes. Integrating patient-reported outcomes into clinical decision-making is essential for value-based oncology care. ● Global Access to Advanced RT Technologies: Ad- dressing disparities in access to hypofractionation, par- ticle therapy, and adaptive RT is critical. Foppele et al. [5] showed that hypofractionation can be implemented in resource-limited settings during the pandemic, and future efforts should focus on expanding access to cost- effective advanced RT technologies worldwide. This includes technology transfer, training, and the develop- ment of simplified yet effective hypofractionated proto- cols suitable for diverse healthcare environments.

  generalfuture workevidence 5/5
  Keywords: response trials adaptive biomarkers future mpmri novel surrogate clinical care outcomes access integration personalized size
• 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 workevidence 5/5
  Keywords: immune tlss tumor clinical tissue remains lymphocyte whether functional evidence dependent spatial paired endpoints immunotherapy

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