Esophageal cancer ranks among the most common and deadly malignancies worldwide, with esophageal squamous cell carcinoma representing the predominant histological subtype in Asia and particularly in China. Radiotherapy, either as definitive treatment or in combination with chemotherapy and surgery, plays a central role in ESCC management. However, patient responses to radiotherapy vary considerably, with some achieving complete pathological response while others show minimal tumor regression despite aggressive treatment.

The ability to predict radiotherapy response before or during treatment would have substantial clinical implications. Patients likely to respond well could proceed with confidence to definitive radiotherapy, while those with predicted poor response might benefit from alternative approaches such as upfront surgery or enrollment in clinical trials testing novel therapeutic combinations. Despite this clear clinical need, reliable biomarkers for radiotherapy response in ESCC remain elusive.

Secretory leukocyte peptidase inhibitor, a small protein produced by epithelial cells, has emerged as a candidate biomarker in multiple cancer types. SLPI exhibits diverse biological functions, including protease inhibition, antimicrobial activity, and modulation of inflammatory responses. In cancer, SLPI has been implicated in tumor progression, metastasis, and treatment resistance through mechanisms involving NF-κB signaling, epithelial-mesenchymal transition, and immune modulation.

This study investigated the role of SLPI as a dynamic biomarker for radiotherapy response in ESCC. The research team analyzed SLPI expression in tumor specimens from ESCC patients before and during radiotherapy, correlating expression levels with treatment outcomes including pathological response, progression-free survival, and overall survival. The dynamic nature of SLPI expression—changing in response to radiation exposure—was a key focus of the investigation.

The findings revealed that baseline SLPI expression was significantly higher in ESCC tumors compared to adjacent normal tissues. More importantly, changes in SLPI expression during the course of radiotherapy correlated with treatment response. Patients whose tumors showed decreased SLPI expression after initial radiation doses were more likely to achieve complete or partial response compared to those with stable or increased SLPI levels.

Mechanistically, the study explored how SLPI influences radiotherapy sensitivity in ESCC cells. In vitro experiments demonstrated that SLPI overexpression protected ESCC cells from radiation-induced apoptosis, while SLPI knockdown sensitized cells to radiation. These effects were mediated through modulation of DNA damage repair pathways and regulation of pro-survival signaling cascades.

The clinical utility of SLPI as a biomarker was further evaluated through statistical modeling. Incorporating SLPI expression dynamics into predictive models improved the accuracy of treatment response prediction compared to clinical factors alone. This suggests that SLPI could complement existing staging systems and help guide personalized treatment decisions.

Several implications arise from these findings. First, SLPI measurement before and early during radiotherapy could identify patients who may benefit from treatment intensification or alternative approaches. Second, targeting SLPI or its downstream effectors might represent a novel strategy for radiosensitization in ESCC. Third, the dynamic biomarker approach exemplified by this study could be extended to other cancers and treatment modalities.

Future research directions include validation of these findings in larger, multi-center cohorts, investigation of SLPI as a predictive biomarker for other treatment modalities such as chemotherapy and immunotherapy, and exploration of therapeutic strategies targeting SLPI in combination with radiotherapy.
DOI
10.1007/s11684-026-1211-5