Solid Tumour Cell-Intrinsic Function of PI3Kδ in Immunotherapy

PI3Kδ is a predominantly leukocyte-enriched class I PI3K consisting of the p110δ catalytic subunit (encoded by PIK3CD) and most commonly the p85α regulatory subunit (encoded by PIK3R1). PI3Kδ is an important regulator of B-cell function and has been the target of extensive drug development efforts for B-cell malignancies, with multiple inhibitors approved for this indication. Based on our pre-clinical studies, PI3Kδ inhibition is now also emerging as an immunotherapy approach for solid tumours. Regulatory T-cells (Treg) are exquisitely sensitive to PI3Kδ inhibition, therefore pharmacological PI3Kδ inhibitors preferentially target the Tregs, rebalancing the immune system in favour of an effector T cell-mediated anti-tumour immune response. This concept is currently under investigation in clinical trials in uveal melanoma and non-small cell lung cancer. Notably, we and others have also observed multiple solid tumour types including glioblastoma, melanoma, breast cancer, prostate cancer, neuroblastoma and hepatocellular carcinoma also express wild-type PIK3CD, often at much higher levels than their non-transformed cell types of origin. Some studies suggest PI3Kδ promotes proliferation in these tumour cells, but this remains unclear with the potential that inhibitors were used at non-PI3Kδ-specific concentrations, and these findings are not consistently confirmed with genetic approaches. This raises the questions of what function PI3Kδ plays in solid tumours and how the use of PI3Kδ inhibitors for immunotherapy will affect the tumour cells themselves via inhibition of cell-intrinsic PI3Kδ. Using highly-selective PI3Kδ inhibitors and CRISPR-Cas9-mediated PIK3CD deletion in solid tumour cell lines, we demonstrate that PI3Kδ inhibition does not affect cell proliferation in these models. However, through both in vitro and xenograft studies, we have identified cancer-relevant roles for PI3Kδ in solid tumours, the implications of which will be presented. Our data suggest the solid tumour cell-intrinsic PI3Kδ expression should be considered to inform PI3Kδ-targeting immunotherapy studies. Citation Format: Sarah E. Conduit, Elena Lopez-Guadamillas, Daniele Morelli, Harriet Howard, Wayne Pearce, Cheryl Scudamore, Bart Vanhaesebroeck. Solid tumor cell-intrinsic function of PI3Kδ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5750.