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TAM Plasticity under androgen deprivation therapy and PARP inhibition in prostate cancer: a multi-omics perspective
Shuangming Chen1, Weiwei Cai2, Chunlin Liu1
1Department of Urology, The Affiliated Taizhou Second People's Hospital of Yangzhou University, Taizhou, Jiangsu, China.
Abstract:
Androgen deprivation therapy (ADT) and next-generation androgen receptor pathway inhibitors (ARPI) are increasingly combined with PARP inhibitors (PARPi) in metastatic prostate cancer (mPCa). These treatments have improved outcomes, yet responses remain variable and often lack durability. Single-cell and spatial multi-omics studies indicate that tumor-associated macrophages (TAMs) strongly influence therapeutic response and form a treatment-shaped continuum of states enriched for TREM2 and SPP1 programs, lipid metabolic activity, hypoxia adaptation, and phagocytic checkpoint signaling within the osteogenic cancer-associated fibroblast (CAF) niche. Macrophages also possess functional androgen receptor (AR) activity, which supports an AR-driven myeloid circuit that promotes immune exclusion during ADT or ARPI therapy. PARP inhibitors stimulate cGAS-STING and induce senescence-associated secretory phenotypes (SASP), leading to an initial type I interferon (IFN) response that ultimately transitions to an MDSC-like immunosuppressive phenotype. These processes converge on common mechanisms of phagocytic control through CD47-SIRPα, MerTK, Axl, CSF1R, and TREM2 and represent therapeutic targets for combination therapies. This review details the combined impact of ADT and PARPi and introduces a multi-omic framework that integrates TREM2 or SPP1 burden, STING activation status, phagocytic checkpoint expression, and HRR or SPOP genotype into a Myeloid Lymphatic Composite Score (MLCS). The MLCS is a scoring tool to assist in timing and selecting therapeutic combinations of ARPI with TREM2 or CSF1R blockade, PARPi with STING modulation, and ARPI with anti-CD47 therapy. Integrating mechanistic and translational data provides a foundation for biomarker-guided regimens capable of converting prostate cancer from an immune-cold disease to an immune-responsive state.
Insights
Combining androgen deprivation therapy (ADT) with PARP inhibitors (PARPi) shows promise in metastatic prostate cancer (mPCa). Understanding myeloid cell dynamics and developing targeted combinations can improve treatment response and overcome resistance.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI) combined with PARP inhibitors (PARPi) are used for metastatic prostate cancer (mPCa).
- Treatment responses in mPCa are variable and often lack durability.
- Tumor-associated macrophages (TAMs) significantly influence therapeutic response and exhibit specific states enriched for TREM2, SPP1, lipid metabolism, hypoxia adaptation, and phagocytic checkpoint signaling within cancer-associated fibroblast (CAF) niches.
Purpose of the Study:
- To review the combined impact of ADT and PARPi in mPCa.
- To introduce a multi-omic framework for integrating myeloid cell dynamics and genetic factors.
- To propose a scoring tool for guiding combination therapies.
Main Methods:
- Review of single-cell and spatial multi-omics studies.
- Analysis of macrophage functional androgen receptor (AR) activity and its role in immune exclusion.
- Examination of PARP inhibitor-induced cGAS-STING activation, SASP, and subsequent immunosuppressive phenotypes.
- Identification of common phagocytic control mechanisms (CD47-SIRPα, MerTK, Axl, CSF1R, TREM2) as therapeutic targets.
Main Results:
- Macrophages exhibit AR activity, promoting immune exclusion during ADT/ARPI therapy.
- PARPi induce type I IFN responses that can transition to an immunosuppressive phenotype.
- Convergent mechanisms of phagocytic control offer therapeutic targets.
- A Myeloid Lymphatic Composite Score (MLCS) framework integrates TREM2/SPP1 burden, STING activation, phagocytic checkpoint expression, and HRR/SPOP genotype.
Conclusions:
- The MLCS can guide the selection and timing of combination therapies, such as ARPI with TREM2/CSF1R blockade, PARPi with STING modulation, and ARPI with anti-CD47 therapy.
- Integrating mechanistic and translational data supports biomarker-guided regimens.
- These approaches aim to convert prostate cancer from an immune-cold to an immune-responsive state.
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