PI3K/AKT/mTOR signaling at the immune checkpoint interface in lung cancer: molecular mechanisms, Tumor–Immune remodeling, therapeutic resistance, and emerging treatment strategies

Abstract

Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have substantially improved the treatment of lung cancer, yet durable responses remain limited by primary and acquired resistance. Increasing evidence identifies the PI3K/AKT/mTOR pathway as a central link between oncogenic signaling, metabolic adaptation, and tumor immune suppression. Genetic and molecular alterations, including PIK3CA activation, PTEN loss, and aberrant EGFR or ALK signaling, can activate this pathway and regulate PD-L1 expression at transcriptional, translational, and post-translational levels. Conversely, tumor-intrinsic PD-L1 signaling can reinforce PI3K/AKT/mTOR activity, promoting proliferation, survival, glycolysis, epithelial–mesenchymal transition, and resistance to therapy. This reciprocal interaction establishes a feedforward circuit that supports lung cancer progression and immune escape. The pathway also reshapes the tumor microenvironment by promoting regulatory T-cell expansion, M2-like macrophage polarization, myeloid-cell recruitment, CD8 + T-cell dysfunction, and resistance to immune checkpoint blockade. 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.