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

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.

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.

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.

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.