The CSF1R/PI3Kδ dual inhibitor JMC14 suppresses angiogenesis in clear cell renal cell carcinoma by reprogramming the tumor microenvironment

Clear cell renal cell carcinoma (ccRCC), a kidney cancer subtype, is characterized by its aggressive nature and limited treatment options, leading to a poor prognosis. We observed elevated levels of CSF1R and PIK3CD in ccRCC tissues. A new CSF1R/PI3Kδ dual inhibitor, JMC14, greatly reduced the growth of xenografts originating from ccRCC A498 cells despite showing only moderate activity against cell proliferation in vitro . Single-cell RNA sequencing of A498 tumors demonstrated that JMC14 altered the tumor microenvironment (TME) by decreasing the presence of immunosuppressive macrophages. JMC14 modulated macrophage polarization towards the M1-like phenotype and inhibited M2 tumor-associated macrophage (TAM)-mediated tumor angiogenesis by decreasing the secretion of IL-8 and VEGF, which might be associated with blocking the STAT3 and NF-κB pathways in macrophages. JMC14 significantly impeded the growth of xenografts derived from ccRCC 786-O cells and patient samples while also decreasing M2 macrophage infiltration and attenuating angiogenesis. Taken together, simultaneously targeting CSF1R and PIK3CD displayed significant efficacy in ccRCC and inhibited tumor angiogenesis via reshaping the TME, providing a promising rationale for the therapy of ccRCC.