Deciphering double-negative prostate cancer: from aggressive subtype to novel therapeutic paradigms.

Double-negative prostate cancer (DNPC), defined by the absence of androgen receptor expression and neuroendocrine markers, represents a clinically aggressive and molecularly distinct subtype of metastatic castration-resistant prostate cancer. Typically emerging after failure of second-generation androgen receptor pathway inhibitors, DNPC portends a dismal prognosis with intrinsic resistance to conventional therapies. This malignancy arises through profound lineage plasticity, driven by epigenetic dysregulation including KMT2C loss and PRC1 complex activation, alongside transcriptional rewiring orchestrated by master regulators like Delta Np63 and KLF5. These alterations dismantle luminal identity, establish compensatory signaling pathways such as FGFR-MAPK and mTORC1-MYC and actively sculpt an immunosuppressive tumor microenvironment, notably through CCL2 chemokine secretion. The resulting phenotype features squamous/basal differentiation, metabolic reprogramming, stemness properties, and early visceral metastasis. Despite molecular characterization revealing recurrent alterations like PTEN and RB1 co-loss and CHD7 amplification, therapeutic translation faces significant hurdles, particularly the difficulty of directly targeting key transcription factors. Innovative strategies are essential, including degrader molecules against master regulators, exploiting vulnerabilities linked to specific genomic losses, combinatorial targeting of parallel survival pathways, and novel immunotherapies aimed at disrupting the immunosuppressive niche. Overcoming diagnostic limitations and designing biomarker-stratified clinical trials are critical next steps. DNPC exemplifies adaptive cancer evolution under therapeutic pressure, demanding multidisciplinary efforts to decipher its complexities and translate these insights into effective therapeutic paradigms for this lethal variant.