Editorial: Radiotherapy for esophageal cancer: Molecular mechanism and novel targets to improve radiosensitivity

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TL;DR

This editorial introduces a Research Topic on radiotherapy for esophageal cancer, highlighting molecular mechanisms of radioresistance and novel targets to improve radiosensitivity. Five research articles are summarized, covering topics such as ELAVL1/HuR knockdown to enhance X-ray efficacy, induction chemotherapy plus concurrent chemoradiotherapy, fiducial marker implantation, and prognostic blood-based markers like the FA score and NLR. The editorial emphasizes the need for combination strategies and precise biomarkers to improve outcomes in esophageal cancer radiotherapy.

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**Background:** Esophageal cancer (EC) is the seventh most common cancer and the sixth leading cause of cancer-related deaths worldwide. Multimodal treatment combining surgery, chemotherapy, and/or radiotherapy is standard for locally advanced EC. Radiotherapy is a mainstay of treatment, but alone it is insufficient: 70%-80% of patients experience uncontrolled local tumor lesions or recurrence within the radiation target area. Radioresistance is polymodal, involving biological alterations within the tumor and its microenvironment. Understanding key molecules in signaling pathways and immune escape is critical to improving radiosensitivity and reducing local recurrence. This editorial introduces a Research Topic comprising five articles on molecular mechanisms and novel targets to improve EC radiosensitivity.

**Methods:** The editorial summarizes five research articles published in the Research Topic. These include experimental studies (cell and animal models), a clinical study, a phase II trial, and retrospective analyses. Specific methods include: (1) Hu et al. investigated ELAVL1/HuR knockdown combined with X-ray in EC cell lines and a xenograft mouse model, assessing proliferation, apoptosis, and Snail mRNA binding via 3'-UTR analysis. (2) Huang et al. conducted a clinical study comparing concurrent chemoradiotherapy (CRT) after induction chemotherapy (IC) versus CRT alone in EC patients, evaluating overall survival (OS) and progression-free survival (PFS). (3) Rochigneux et al. performed a monocentric phase II study (FIDUCOR-study, NCT02526134) evaluating fiducial marker (FM) implantation under endoscopic ultrasound for CRT in EC, measuring growth-tumor-volume-dimension modification. (4) Wang et al. conducted a retrospective study of 154 esophageal squamous cell carcinoma (ESCC) patients who underwent concurrent radiochemotherapy, analyzing pretreatment plasma fibrinogen and serum albumin levels (FA score) as a prognostic marker. (5) Another Wang et al. study assessed peripheral blood inflammatory and nutritional indexes—platelet lymphocyte ratio (PLR), neutrophil lymphocyte ratio (NLR), lymphocyte monocyte ratio (LMR), systemic inflammation response index (SIRI), pan-immune-inflammation value (PIV), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)—in locally advanced gastric cancer (LAGC) patients treated with adjuvant chemoradiotherapy after D2 dissection.

**Key Results:** (1) Hu et al.: Downregulation of HuR combined with X-ray had a significantly stronger effect on EC cell proliferation and apoptosis compared to X-ray alone, validated in a xenograft mouse model. Mechanistically, HuR binds the 3'-UTR of Snail mRNA, stabilizing it and elevating Snail protein levels. (2) Huang et al.: IC plus CRT showed enhanced efficacy over CRT alone, with longer OS and PFS in the combination group. (3) Rochigneux et al.: FM implantation under endoscopic ultrasound resulted in a 100% modification of growth-tumor-volume-dimension, demonstrating applicability in EC treatment. (4) Wang et al. (FA score study): Among 154 ESCC patients, a higher pretreatment FA score was associated with poorer treatment effect and shorter median OS. (5) Wang et al. (LAGC study): Among the inflammatory/nutritional indexes evaluated, NLR was the best marker for predicting survival in LAGC patients treated with adjuvant chemoradiotherapy after D2 dissection; a higher NLR was significantly related to shorter OS and disease-free survival.

**Clinical Implications:** The findings highlight several promising strategies to improve EC radiotherapy outcomes. Combining HuR knockdown with radiotherapy may enhance radiosensitivity by targeting Snail-mediated pathways. The clinical benefit of IC plus CRT over CRT alone supports intensified neoadjuvant approaches. FM implantation offers a practical method to improve radiotherapy precision. The FA score provides a simple, blood-based prognostic tool for ESCC patients undergoing radiochemotherapy, potentially guiding treatment selection. In LAGC, NLR emerges as a valuable prognostic marker. Collectively, these studies underscore the importance of molecular targeting and biomarker-driven patient stratification to optimize radiotherapy in EC and related gastrointestinal cancers.