Apolipoprotein E promotes primary resistance to AR-targeted therapy via inducing TRIM25-mediated AR ubiquitination and sensitizes immunotherapy in prostate cancer

<b>Rationale:</b> Prostate cancer (PCa) growth is facilitated by the androgen receptor (AR) and its downstream signaling pathways, making AR-targeted therapy crucial for treating advanced stages. Despite this, the response to AR-targeted therapies is inconsistent, with a significant proportion of patients even exhibiting unresponsiveness to therapy from the outset, known as primary resistance. Therefore, a refined categorization framework is imperative for the timely detection of resistant phenotypes and the exploration of novel therapeutic avenues. <b>Methods:</b> Tissue microarrays and clinical cohorts were employed to delineate the impact of APOE on the prognostic outcomes and therapeutic resistance in PCa patients. Employing flow cytometry, immunoprecipitation, and mass spectrometry, we dissected the molecular underpinnings of APOE's role in conferring resistance to AR-targeted interventions. Single-cell RNA sequencing elucidated the intricate transcriptomic profiles of PCa with elevated APOE expression. Additionally, the therapeutic potential of anti-PD-L1 agents in treating PCa with APOE induction was rigorously assessed. <b>Results:</b> In this study, we elucidated the pivotal role of APOE in mediating primary resistance to AR-targeted therapy in PCa through the suppression of AR signaling pathways. Mechanistically, APOE was found to enhance the ubiquitination and subsequent degradation of AR by mediating the interaction between the E3-ligase TRIM25 and AR, concurrently dampening the transcriptional activity of AR. Additionally, elevated APOE expression was correlated with an augmented response to anti-PD-L1 treatment, hinting at the therapeutic advantage of immunotherapy in APOE-high PCa contexts. <b>Conclusions:</b> APOE expression could serve as a prognostic biomarker, pivotal for forecasting responses to both AR-targeted therapy and immunotherapy, thereby offering an innovative strategy for the personalized selection of treatment modalities in PCa.