Tackling tumor hypoxia: advances in breaking the oncogenic HIF-1α-p300/CBP alliance.

The ability of tumor cells to survive under low-oxygen conditions is largely attributed to the hypoxia-inducible factor-1 (HIF-1) pathway, in which HIF-1α forms a functional complex with the transcriptional co-activators p300/CBP. This interaction drives the expression of genes that promote angiogenesis, metabolic reprogramming, and immune evasion and correlates with advanced disease and poor outcomes in diverse cancer types. In recent years, extensive efforts have sought to disrupt the HIF-1α-p300/CBP axis, leveraging strategies that include blocking protein-protein binding, inhibiting acetyltransferase activity, and modulating post-translational modifications that stabilize HIF-1α. A range of small-molecule inhibitors, derived either synthetically or from natural sources such as fungal metabolites and plant polyphenols, have demonstrated efficacy in preclinical cancer models by attenuating tumor hypoxia adaptations and sensitizing malignant cells to chemotherapies and radiotherapies. Although many of these compounds exhibit favorable anti-tumor activity, issues of specificity, drug delivery, toxicity, and potential resistance mechanisms remain. This review highlights the current understanding of HIF-1α-p300/CBP biology, examines small-molecule compounds that target this critical transcriptional interface, and evaluates preclinical evidence validating their therapeutic promise. We also discuss emerging challenges in translating these findings to clinical practice, emphasizing combination treatment strategies, biomarker-driven patient selection, and refined drug formulations to optimize efficacy and safety. By offering a detailed overview of the HIF-1α-p300/CBP landscape, this review underscores the potential of disabling tumor hypoxia responses as an innovative approach to combat cancer progression.