The PI3K/Akt signaling pathway in cancer immune evasion and its therapeutic implications

Immune checkpoint blockade has changed the treatment landscape for several malignancies, yet primary resistance, adaptive resistance and incomplete immune reactivation remain common across solid tumors. The phosphoinositide 3-kinase (PI3K)/Akt pathway is usually introduced as a canonical oncogenic signaling axis that controls proliferation, survival, metabolism and therapeutic resistance. A broader view is now needed because PI3K/Akt signaling also shapes the immune phenotype of malignant tissues. In tumor cells, pathway activation can increase immune checkpoint ligand expression, reinforce immune-cold states, influence broader immune-recognition programs and support secretion of immunosuppressive mediators. In the tumor microenvironment, PI3K isoforms and downstream Akt-mTOR signaling regulate macrophage polarization, myeloid-derived suppressor cell activity, regulatory T-cell function, cytotoxic T-cell fitness and metabolic competition. These mechanisms create a convergence point between tumor-intrinsic oncogenic signaling and non-malignant immune-cell dysfunction. This review summarizes the evidence linking PI3K/Akt signaling to immune evasion, highlights tumor-type-specific patterns involving PTEN loss and PIK3CA alterations, and discusses therapeutic strategies that combine PI3K/Akt-pathway inhibition with immune checkpoint inhibitors, radiotherapy, metabolic intervention or selective delivery technologies. The central conclusion is that PI3K/Akt should be viewed not only as a growth pathway but also as a context-dependent immune-regulatory convergence point, while the causal strength of individual pathway–phenotype relationships varies across experimental systems and tumor contexts.