Table 1_PI3K/AKT/mTOR signaling at the immune checkpoint interface in lung cancer: molecular mechanisms, Tumor–Immune remodeling, therapeutic resistance, and emerging treatment strategies.docx

This review critically examines the bidirectional crosstalk between PI3K/AKT/mTOR and PD-1/PD-L1 signaling in lung cancer and summarizes the molecular regulators that connect these pathways. We further discuss therapeutic strategies designed to disrupt this network, including PI3K, AKT, and mTOR inhibitors; targeted therapies; chemotherapy and radiotherapy combinations; antiangiogenic approaches; nanomedicine; extracellular-vesicle-based delivery; cell-based interventions; and natural compounds.

Although preclinical evidence supports combining pathway inhibition with immune checkpoint blockade, clinical translation is challenged by pathway complexity, context-dependent regulation of PD-L1, systemic toxicity, and the absence of validated predictive biomarkers. Biomarker-guided patient selection, optimized dosing and sequencing, and selective targeting of tumor- or immune-cell-specific pathway components will therefore be essential for converting this mechanistic rationale into durable clinical benefit.</p>