PHF8 (PHD finger protein 8) is a histone lysine demethylase that removes repressive methyl marks from chrX, primarily targeting H3K9me1/2, H3K27me1/2, and H4K20me1 1. As a transcriptional activator, PHF8 recognizes H3K4me3 through its PHD domain, which enhances its demethylase specificity and activity 1. PHF8 plays essential roles in cell cycle progression via G1-S transition control and rDNA transcription by activating RNA polymerase I 1. Beyond developmental functions, PHF8 regulates transcription recovery following DNA double-strand break repair by reversing H3K9me2-mediated repression 2. Clinically, PHF8 mutations cause X-linked intellectual developmental disorder (Siderius type) and are implicated in neurodevelopmental disorders affecting autophagy regulation 3. PHF8 is significantly upregulated in multiple cancers including colorectal cancer, renal cell carcinoma, and melanoma, where it promotes tumor progression and immune escape by upregulating PD-L1 and KRAS/BRAF expression 45. Notably, PHF8 deletion activates a viral mimicry response through retrotransposon activation, enhancing anti-tumor immunity and immunotherapy sensitivity 6. PHF8 also regulates TGFβ signaling to promote melanoma metastasis 7. These findings establish PHF8 as both a developmental regulator and emerging therapeutic target for cancer immunotherapy and epigenetic disorders.