Abstract PI3Kδ is a key lymphocyte signaling hub for manipulating antitumor immunity. In cancer, most work has centered on inhibiting PI3Kδ, particularly in regulatory T cells, to relieve immunosuppression and enhance effector T cell control of established tumors. Yet lung metastasis remains a leading cause of cancer mortality, and the impact of PI3Kδ modulation on metastatic outgrowth remains incompletely understood. Inspired by gain-of-function PIK3CD mutations that cause activated PI3Kδ syndrome (APDS), we ask whether enhancing PI3Kδ signaling can be harnessed to prevent melanoma lung metastases. Here, we demonstrate that hyperactivation of PI3Kδ confers robust protection against pulmonary melanoma metastases in a CD4+ T cell - dependent manner that drives IFNγ-mediated tumor cell senescence. We employed mice with germline or conditional hyperactive PI3Kδ, challenged intravenously with B16F10 melanoma to establish lung metastasis. Cell-specific Cre systems identified critical immune populations mediating metastasis rejection. Single-cell RNA-seq and spectral cytometry defined immune remodeling, while depleting and neutralizing antibodies as well as CRISPR-edited melanoma lines revealed underlying mechanism. Germline hyperactive-PI3Kδ mice developed markedly fewer lung metastases than wild-type controls, and inducible activation of hyperactive PI3Kδ in the hematopoietic compartment was sufficient to confer protection. Protection was dependent on CD4+ T cells - CD4+ T cell specific PI3Kδ hyperactivation recapitulated germline protection, while B cell, NK cell and CD8+ T cell specific PI3Kδ hyperactivation did not. Antibody depletions confirmed that CD4+ depletion abolished protection while CD8+ depletion had no effect. Hyperactive PI3Kδ CD4+ T cells showed enhanced Th1 differentiation with increased IFNγ and IFNγ-neutralization eliminated the protection against metastasis. Mechanistically, tumor control required IFNGR1/JAK1 signaling in cancer cells but not TNFR1, and operated independent of tumor MHC-I or MHC-II expression. The protective mechanism converged on IFNγ-induced tumor senescence, as lung metastases from hyperactive-PI3Kδ mice displayed increased SA-β-gal activity, indicating that CD4+ T cells halt metastatic progression by enforcing tumor cell senescence. Our findings reveal a novel protective axis where hyperactive PI3Kδ signaling in CD4+ T cells drives a type 1-skewed pulmonary anti-metastasis microenvironment. This elevates CD4+ T cells from "helpers" to anti-metastatic effectors using IFNγ-dependent tumor-intrinsic senescence to achieve durable immune control. These results reveal hyperactive PI3Kδ as a double-edged sword: while pathogenic in APDS, it reinforces immune surveillance of metastasis, offering new therapeutic avenues for preventing metastatic progression by enhancing PI3Kδ signaling. Citation Format: Leqi Tang, Grace Cooper, Linsey Porter, Seung joon Kim, Erick Armingol, Oliver Burton, James E. Thaventhiran, Walid T. Khaled, Roser Vento-tormo, Rahul Roychoudhuri, Klaus Okkenhaug. PI3Kδ in CD4+ T cells protects against lung metastases through IFNγ-induced tumor senescence 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 158.
Tang et al. (Fri,) studied this question.