PI3Kdelta in CD4⁺ T cells protects against lung metastases through IFNgamma-induced tumor senescence

PI3Kdelta is a key lymphocyte signaling hub for manipulating antitumor immunity. In cancer, most work has centered on inhibiting PI3Kdelta, 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 PI3Kdelta modulation on metastatic outgrowth remains incompletely understood. Inspired by gain-of-function PIK3CD mutations that cause activated PI3Kdelta syndrome (APDS), we ask whether enhancing PI3Kdelta signaling can be harnessed to prevent melanoma lung metastases. Here, we demonstrate that hyperactivation of PI3Kdelta confers robust protection against pulmonary melanoma metastases in a CD4 + T cell - dependent manner that drives IFNgamma-mediated tumor cell senescence. We employed mice with germline or conditional hyperactive PI3Kdelta, 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-PI3Kdelta mice developed markedly fewer lung metastases than wild-type controls, and inducible activation of hyperactive PI3Kdelta in the hematopoietic compartment was sufficient to confer protection. Protection was dependent on CD4 + T cells - CD4 + T cell specific PI3Kdelta hyperactivation recapitulated germline protection, while B cell, NK cell and CD8 + T cell specific PI3Kdelta hyperactivation did not. Antibody depletions confirmed that CD4 + depletion abolished protection while CD8 + depletion had no effect. Hyperactive PI3Kdelta CD4 + T cells showed enhanced Th1 differentiation with increased IFNgamma and IFNgamma-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 IFNgamma-induced tumor senescence, as lung metastases from hyperactive-PI3Kdelta mice displayed increased SA-beta-gal activity, indicating that CD4 + T cells halt metastatic progression by enforcing tumor cell senescence. Our findings reveal a novel protective axis where hyperactive PI3Kdelta 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 IFNgamma-dependent tumor-intrinsic senescence to achieve durable immune control. These results reveal hyperactive PI3Kdelta 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 PI3Kdelta signaling.