PI3Kγ-dependent macrophage reprogramming overcomes microenvironmental tumor protection in sunitinib-challenged renal cancer

In sunitinib-treated renal cancer, tumor-associated macrophages (TAMs) can support tumor survival while suppressing antitumor immunity, but whether both effects can be reversed simultaneously is unclear. We identify phosphoinositide 3-kinase γ (PI3Kγ) as a macrophage-associated target and develop a protease-responsive, macrophage-directed nanocarrier (IMNMP) delivering the PI3Kγ inhibitor eganelisib (IPI-549). Sunitinib-conditioned renal cancer cells induced a tumor-supportive macrophage state with increased PI3Kγ and enhanced tumor cell protection. Genetic PI3Kγ silencing or IMNMP attenuated this protection, promoted macrophage costimulatory/inflammatory programs and enhanced CD8⁺ T-cell responses. In vivo, IMNMP plus sunitinib improved tumor control and produced an immunostimulatory microenvironment with increased macrophage costimulation and CD8⁺ T-cell infiltration. Bulk and single-cell transcriptomics linked treatment to antigen-presentation, interferon-response and effector immune programs in tumor-associated myeloid cells. Together, PI3Kγ-dependent macrophage function is an actionable component of sunitinib-treated renal cancer, and macrophage-directed PI3Kγ inhibition may simultaneously reduce microenvironmental tumor protection and strengthen antitumor immunity.