KIAA0101, also known as proliferating cell nuclear antigen (PCNA) clamp-associated factor (PCLAF), is a small PCNA-interacting protein linking DNA replication, DNA damage tolerance, cell-cycle progression, and genome maintenance. Aberrant KIAA0101 expression occurs across multiple human malignancies and is frequently associated with aggressive clinicopathological features, therapy resistance, and poor survival. Beyond its canonical role as a proliferation-associated PCNA cofactor, emerging evidence obtained from bulk transcriptomics, single-cell sequencing, and spatially resolved analyses suggests that KIAA0101-high tumor states mark proliferative, stem-like, immune-excluded, and treatment-resistant ecosystems. However, research in this field remains limited by descriptive correlations, small retrospective cohorts, isoform-blind assays, and incomplete mechanistic validation. In this review, we synthesize current evidence on the structural features, regulatory networks, cellular functions, disease-specific roles, immune-microenvironmental associations, and translational relevance of KIAA0101 in cancer. We emphasize that its immune-related effects are more plausibly mediated through indirect regulatory routes, including NF-κB- and Wnt/β-catenin-associated programs, rather than through the direct transcriptional control of immune checkpoint genes. We further discuss therapeutic strategies targeting the KIAA0101-PCNA interface, KIAA0101 degradation, RNA interference/CRISPR-based suppression, and rational combinations with DNA damage response inhibitors or approved targeted agents. Future work should prioritize isoform-resolved detection, non-PCNA interactome mapping, immune-competent functional models, and biomarker-driven validation to determine whether KIAA0101 can be advanced from a cancer-associated molecule to a clinically actionable biomarker or therapeutic vulnerability.