p21 (CDKN1A) acts as prognostic biomarker, sensitizing cancer cells to therapy and modulating TME immunity

The protein p21 (encoded by CDKN1A) is a canonical regulator of cell cycle arrest and genomic stability, crucial for preventing uncontrolled cell proliferation. However, its precise functional spectrum within the complex tumor microenvironment (TME), particularly at single-cell resolution, remains poorly understood. Current cancer therapies often face challenges like resistance and limited efficacy, highlighting the need for novel targets and strategies that leverage intrinsic cellular mechanisms like p21 to improve patient outcomes and overcome therapeutic hurdles.

Researchers conducted an integrative multiomics analysis combining bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), and functional assays across multiple cancer types. Publicly available datasets were utilized to evaluate CDKN1A expression, immune infiltration, and signaling pathways. Functional validation involved silencing or overexpression of p21 in several cancer cell lines. In vitro drug-sensitivity assays assessed the impact of p21 overexpression on sensitivity to targeted and chemotherapy agents, while coculture experiments explored macrophage polarization's influence on p21-mediated tumor cell inhibition.

Pancancer analysis revealed that CDKN1A expression is frequently dysregulated across various tumor types and significantly associated with patient prognosis. scRNA-seq data further demonstrated that CDKN1A was preferentially enriched in nonmalignant epithelial cells and varied along an inferred malignant epithelial transcriptional continuum. Computational cell-cell communication analysis suggested inferred ligand-receptor associations involving extracellular matrix-related and immune-associated signaling pathways. Functionally, p21 overexpression consistently suppressed tumor cell proliferation, induced senescence and apoptosis, and reduced migratory capacity across multiple cancer cell lines. In vitro drug-sensitivity assays showed that p21 overexpression was associated with enhanced sensitivity to targeted therapy and chemotherapy agents, evidenced by reduced IC50 values. Additionally, p21 regulated immune-related molecules, including ICOS, TGFB1, and PDCD1. Coculture experiments revealed that M1 macrophages enhanced p21-mediated tumor cell inhibition, while M2 macrophages attenuated this effect.

p21 overexpression significantly suppressed tumor cell proliferation, induced senescence and apoptosis, and reduced migratory capacity across multiple cancer cell lines, indicating a potent tumor-suppressive role.