IFI44L modulates chemoradiotherapy sensitivity and CD8+ T cell infiltration in colorectal cancer.

OBJECTIVE: Chemoradiotherapy (CRT) represents a cornerstone treatment for colorectal cancer (CRC), yet heterogeneous responses to CRT in treatment response remain a major clinical challenge. Increasing evidence suggests that the tumor immune microenvironment (TME) especially intratumoral CD8+ T cells plays an important role in determining CRT efficacy; however, the molecular mechanisms linking tumor-derived factors to immune-mediated treatment sensitivity remain poorly understood. Here, we aimed to identify and characterize regulators of CRT response and the underline mechanisms in CRC. METHODS: Transcriptomic profiling of rectal cancer cohorts was performed to identify genes associated with CRT response, followed by pathway enrichment analyses to explore potential biological mechanisms. The functional role of interferon-induced protein 44-like (IFI44L) was investigated using in vitro assays and in vivo immunodeficient NSG and immunocompetent BALB/c mouse models to distinguish tumor cell-autonomous from immune-dependent effects. RNA sequencing, immune infiltration analysis, chemotaxis assays, immunofluorescence staining, and enzyme-linked immunosorbent assays (ELISA) were further performed to elucidate the underlying molecular mechanisms. RESULTS: IFI44L is identified as a candidate gene associated with CRT response through multi-cohort transcriptomic analysis. IFI44L overexpression did not directly alter CRC cell proliferation or CRT response in vitro, nor did it affect tumor growth following CRT in immune-deficient NSG mice. In contrast, IFI44L significantly enhanced CRT efficacy in immunocompetent BALB/c models, suggesting that its sensitizing effect was in an immune-dependent manner. Mechanistically, IFI44L promoted the expression and secretion of the T cell-attracting chemokine CCL5, leading to increased intratumoral CD8+ T cell infiltration and enhanced CRT response. CONCLUSIONS: Our findings identify IFI44L as an immune-dependent regulator of CRT sensitivity in CRC. By promoting CCL5-mediated CD8+ T cell recruitment, IFI44L links tumor-intrinsic molecular alterations with antitumor immune responses and may represent a potential biomarker or therapeutic target for improving CRT efficacy.