Backgrounds: Colon cancer is a leading cause of fatalities worldwide. The human plant homeodomain (PHD) finger protein 1 (PHF1) has been reported to play roles in various biological processes and the progression of several types of cancer. This study aims to investigate the impact of PHF1 on the progression of colon cancer and explore the underlying mechanisms. Methods: The differential expression of PHF1 in colon cancer tissues and cells was validated using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot analyses. To assess the impact of PHF1 on colon cancer and the cell cycle pathway, as well as the reciprocal effect of cyclin-dependent kinase inhibitor 1A (CDKN1A)-mediated cell cycle regulation on PHF1 in colon cancer, the expression levels of PHF1 and cyclin-dependent kinase inhibitor 1A (CDKN1A) were modulated through specific small interference (si)RNA transfection. Cell proliferation was assessed using colony-forming and cell counting kit-8 (CCK-8) assays, while cell apoptosis was evaluated through the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and enzyme-linked immunosorbent assay (ELISA) to detect Bcl-2 (B-cell Leukemia/Lymphoma 2) and Bax (Bcl-2 associated X protein). Cell metastasis ability was determined using trans-well assays for cell migration and invasion, as well as lipid formation. Human Colorectal Carcinoma Cells (LOVO) were transfected and co-cultured with peripheral blood mononuclear cells (PBMCs) to elucidate the effects of PHF1 and the cell cycle on immunotherapy. This involved assessing the ratio of cells killed by immune cells, the proliferation of CD8⁺ T cells, and the percentages of CD107a⁺ and IFN-γ⁺ T cells. Results: PHF1 was found to be significantly overexpressed in both colon cancer tissues (p < 0.01) and cells (p < 0.01), demonstrating its capacity to activate the cell cycle pathway (p < 0.001). The upregulation of PHF1 led to increased cancer cell proliferation, invasion, and lipid formation (p < 0.001), while simultaneously decreasing colon cancer cell apoptosis (p < 0.001). Importantly, these effects were reversed when the cell cycle was suppressed (p < 0.01). Furthermore, in co-culture experiments where colon cancer cells with upregulated PHF1 were exposed to PBMCs, fewer colon cancer cells were killed (p < 0.001). There was also a reduction in the proliferation of CD8⁺ T cells (p < 0.001) and lower percentages of both CD8⁺ CD107a⁺ T cells (p < 0.001) and CD8⁺ IFN-γ⁺ T cells (p < 0.001). Notably, these outcomes were all reversed when the cell cycle pathway was suppressed (p < 0.001). Conclusions: PHF1 emerges as a potential marker for colon cancer, contributing to the progression of the disease through the activation of the cell cycle pathway. The suppression of PHF1 enhances the susceptibility of colon cancer to immunotherapy. These findings underscore the significance of PHF1 and the cell cycle pathway as viable targets for colon cancer treatment. Combining these targets with immunotherapy holds promise for the development of effective therapeutic strategies against colon cancer.