A syngeneic mouse model of metastatic hormone-naive prostate cancer provides a platform for studying combination immunotherapy

Abstract Metastatic hormone-naive prostate cancer (mHNPC) refers to a small subset of diagnosed prostate tumors and presents very high mortality and poor response to available therapies. Despite its clinical relevance, we lack immunocompetent models that are both androgen-dependent and reliably metastatic, limiting the implementation of translational research strategies. Here we develop and characterize PL051, a syngeneic, bioluminescence tractable prostate carcinoma cell line derived from a Pten / Lkb1 double knockout genetic mouse model that reproducibly engrafts orthotopically in C57BL/6 mice, maintains androgen-receptor (AR) signaling, and consistently disseminates to soft tissues and bone. PL051 preserves Pten / Lkb1 loss and PI3K–AKT activation, shows intact AR responsiveness in vitro, and responds to AR-pathway intensification in vivo. We provide two complementary proof-of-concept evidence for the preclinical potential of this model. On one hand, we show the therapeutic benefit of combining androgen signaling inhibition and anti-PD1 treatment. On the other hand, we provide evidence showing that co-targeting myeloid cells with a CSF1R inhibitor further enhances therapeutic activity of checkpoint blockade by depleting suppressive macrophages and boosting T-cell recruitment. Together, this preclinical model fills a critical gap for studying mHNPC biology and provides a scalable, immune-competent model for testing rational combinatorial treatments.