Chromosome 1 Open Reading Frame 35 Drives Colorectal Cancer Progression by Enhancing Tumor‐Intrinsic Proliferation and CD8 ⁺ T Cell Suppression

ABSTRACT The functional significance of Chromosome 1 open reading frame 35 (C1orf35) in colorectal cancer (CRC) remains poorly characterized. This study investigates its oncogenic role and underlying mechanisms. We report that C1orf35 is frequently upregulated in CRC clinical specimens, and its elevated expression correlates strongly with advanced tumor stage and serves as an independent prognostic indicator for reduced overall survival. Functional assays, including experiments in patient‐derived organoids, demonstrate that C1orf35 is essential for driving tumor cell proliferation, migration, and expansion. Mechanistically, we identify C1orf35 as an upstream activator of the transcription factor c‐Myc. This activation triggers the transcriptional upregulation of the metabolic enzyme pyrroline‐5‐carboxylate reductase 2 (PYCR2), a key node in proline biosynthesis that facilitates tumor growth. Furthermore, we uncover a distinct, non‐cell‐autonomous function of C1orf35 in shaping the tumor immune microenvironment. Through c‐Myc, C1orf35 impairs the cytotoxic function of tumor‐infiltrating CD8 + T cells. This inverse spatial relationship between C1orf35 expression and CD8 + T‐cell infiltration is validated by multiplex immunohistochemistry in human CRC tissues. Thus, our work defines C1orf35 as a dual‐function oncoprotein that promotes CRC progression by coordinately enhancing tumor‐intrinsic growth via the c‐Myc/PYCR2 axis and fostering an immune‐suppressive niche. These findings nominate C1orf35 as a promising multi‐faceted therapeutic target and prognostic biomarker in CRC.