Phosphoinositide-3-kinase δ as an immune check-pathway in cancer Immunology. Therapeutic prospects.

Abstract

Introduction: Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cellular processes, predominantly within the immune system, and its dysregulation is implicated in inborn errors of immunity, including Activated PI3 Kinase Delta Syndrome (APDS), and various malignancies, including hematological and solid tumors. Given PI3Kδ's predominant expression in leukocytes, its aberrant activation not only promotes tumor growth but also enables immune evasion, underscoring its importance as an 'immune-check pathway,' especially in immune-rich tumor microenvironments.

Areas covered: This review examines the oncogenic role of PI3Kδ signaling, emphasizing its contribution to immune evasion, tumor proliferation, survival, and metastasis across different cancers. A bibliographic search was conducted in PubMed, Science Direct, MEDES and SciELO using specific criteria for articles published until 2023.

Expert opinion: PI3Kδ signaling can be conceptualized as an immune check pathway, reinforcing its potential as a therapeutic cancer target. Recent clinical trials using PI3Kδ inhibitors have shown efficacy across various cancers (hematological, breast, gynecologic, and digestive cancers), suggesting their applicability beyond APDS and primary malignancies. This approach could prevent cancer-linked immunodeficiency, providing dual therapeutic and prophylactic benefits. Future research should explore PI3Kδ inhibitors as a comprehensive strategy for managing cancer progression and associated immune dysfunction, ultimately improving patient outcomes.