S2546
Radiobiology - Microenvironment
ESTRO 2026
vitro and in vivo, with the goal of improving patient outcomes. Material/Methods: RP was induced by pelvic-restricted X-irradiation (25 Gy) and mice received oral I3C (75 mg/kg) three times weekly. At endpoint, rectal stenosis was evaluated via colonoscopy, following by H&E and Masson staining to assess mucosal damage. Metabolomics and bulk transcriptome sequencing were performed to clarify how I3C alleviate RP. Results: Following RP induction[4] (Figure 1A), we performed fecal metabolomics in controls (n=12) and RP mice (n=11). Using a standard metabolomics workflow, we identified indole-3-carbinol (I3C) as the most significantly altered metabolite within the top GSEA- enriched metabolic pathway. Our results demonstrated that I3C significantly decreased in RP mice compared to the control group (Figure 1B) and might be a leading RP-depleted fecal metabolite.We administered I3C or vehicle to RP mice during disease progression. Subsequently, Bulk RNA-seq of rectal tissue followed by pathway enrichment identified collagen fiber formation and extracellular-matrix organization as the top downregulated pathways, implicating fibrotic programs as major targets of I3C (Figure 2A). I3C improved colonoscopic motility and wall compliance and reduced mucosal fibrosis. Histologically, we observed preserved epithelium, decreased Masson-positive collagen, and lower expression of type I collagen (Figure 2B). These data indicate that I3C mitigates RP primarily by attenuating pathological intestinal fibrosis. Recent studies suggested that, under injurious stimuli (radiation), macrophages could undergo MMT, thereby promoting fibrotic remodeling. MMT has been implicated in cardiac and renal fibrosis[5, 6], but its role in intestinal injury remains unclear. We therefore hypothesized that I3C alleviates RP by restraining MMT. Immunofluorescence co-localization revealed submucosal cells co-expressing F4/80 and α -SMA, supporting the presence of MMT in RP. Notably, dietary I3C markedly reduced the proportion of F4/80+ α -SMA+ cells at injury sites (Figure 2C), indicating that I3C limits macrophage MMT and suppresses pathological fibrosis in RP.
Conclusion: FAP+ CAF enrichment in MIBC may be detrimental to radiotherapy outcomes via immunosuppressive mechanisms and pro-tumour crosstalk with cancer cells. Future work targeting FAP+ CAFs could improve radiotherapy responses. References: 1. Pereira et al., iNOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy. Cancer Res, 20202. Nicolas et al., Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer. Cancer Cell, 20223. James et al., Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer. New England Journal of Medicine, 20124. Zeegers et al., The West Midlands Bladder Cancer Prognosis Programme: rationale and design. BJU Int, 20105. Bull et al., MuSpAn: A Toolbox for Multiscale Spatial Analysis. BioRxiv. 20246. Wershof et al., A FIJI macro for quantifying pattern in extracellular matrix. Life Sci Alliance, 2021 Keywords: cancer-associated fibroblasts, bladder cancer, RT Dietary indole-3-carbinol as a candidate therapy for radiation proctitis via inhibiting macrophage- to-myofibroblast transition Lekun Fang, Guangyuan Miao, Zhuokai Zhuang, Wencong Wang, Junyan Feng, Manqi Meng, Shaomin Zou Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Purpose/Objective: Pelvic radiotherapy is integral to cancer care yet often injures the adjacent intestine and 5–20% of patients develop radiation proctitis (RP) with epithelial injury and fibrosis [1-3]. Despite its clinical burden, effective therapies for radiation proctitis (RP) remain limited. We aim to define actionable targets and effective interventions for RP and to validate their efficacy in Digital Poster Highlight 2001
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