The implied dysregulated RKIP-hypoxia axis in cancer and immune evasion: Clinical implications

The Raf kinase inhibitor protein (RKIP) functions as both a metastasis suppressor and immune enhancer, exerting its influence over several key oncogenic signaling pathways, including the MAPK, NF-κB, and PI3K pathways. Recent studies have highlighted a potential interplay between RKIP and hypoxia-inducible factors (HIFs), particularly in the hypoxic tumor microenvironment (TME). Hypoxia is known to reprogram cellular metabolism, enhance angiogenesis, and facilitate immune escape. Through analysis of cross-talk signaling pathways between RKIP and HIFs, we establish the presence of a dysregulated RKIP-hypoxia axis in cancer. Notably, many cancers simultaneously express low levels of RKIP and high levels of HIFs an expression pattern that strongly correlates with the emergence of immune evasion mechanisms. Herein, we report on the mechanisms by which this dysregulated axis mediates immune evasion. These include the molecular regulations of RKIP and HIFs expressions, and the low expression of RKIP and high expression of HIFs in several cancers. We report on the mechanisms underlying immune evasion by the RKIP-hypoxia axis by examining various factors intimately involved in immune evasion, such as the upregulation of PD-L1, matrix metalloproteinases (MMPs), anti-apoptotic molecules, CD47, and the enhanced frequencies of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophage (TAM) polarization, and decreased antigen presentation. Thus, hypoxia-induced repression of RKIP establishes a feedforward loop that sustains immune evasion and tumor aggressiveness. Therapeutically, we propose that targeting the RKIP-hypoxia axis offers a new strategy to restore immune surveillance and counteract tumor progression. We present various means to target the inhibition of hypoxia as well as the induction of RKIP. Elucidating the molecular crosstalk between RKIP and hypoxic stress responses opens a new paradigm for strategies that enhance the efficacy of immunotherapies and overcome tumor resistance.