ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
Reversal of Lactate and PD-1-mediated Macrophage Immunosuppression Controls Growth of PTEN/p53-deficient Prostate Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers, 1 of them a synthesis that pooled it.
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Who cites it
110 citing papers in PubMed, 1 synthesis or guideline pooled it, 114 citations in OpenAlex.
- Mapping research trends in macrophage polarization and immunotherapeutic potential in prostate cancer: a bibliometric and visual analysis.Frontiers in oncology · 2026Pooled it
- Tumor‑immune spatiotemporal co‑evolution: A new paradigm for understanding and overcoming therapy resistance in metastatic castration‑resistant prostate cancer (Review).International journal of molecular medicine · 2026Review
- KAT5-mediated HSPA1A lactylation drives immunotherapy resistance by inhibiting STAT1 degradation in esophageal squamous cell carcinoma.Oncogene · 2026Article
- Mechanistic Links Between Natural Bioactive Molecules and Tumor Immune Microenvironment States in PD-1/PD-L1 Resistance.Biomedicines · 2026Review
- Lactylation-driven therapeutic resistance in cancer: Mechanisms and therapeutic opportunities.Genes & diseases · 2026Review
- Clinical and genomic predictors of sipuleucel-T outcomes in men with metastatic androgen pathway modulator resistant prostate cancer.Research square · 2026Article
- Decoding the Raf-Mek-Erk-Rsk pathway in prostate cancer: from molecular mechanisms to clinical opportunities.British journal of cancer · 2026Review
- Lysine lactylation-mediated post-translational modification: Molecular mechanisms and therapeutic target exploration in tumour drug resistance.Clinical and translational medicine · 2026Review
- Novel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review).International journal of oncology · 2026Review
- Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances.Signal transduction and targeted therapy · 2026Review
- Decoding the CAF-TAM axis: multi-omics dissection and therapeutic targeting of stromal-immune crosstalk in the tumor microenvironment.Cell death & disease · 2026Review
- Targeting phase separation: a new strategy to disrupt the stromal-immune axis in colorectal cancer.Cell communication and signaling : CCS · 2026Review
- Melittin enhances PD-L1 blockade in prostate cancer by inhibiting M2 macrophage polarization and recruitment.World journal of surgical oncology · 2026Article
- Cancer Cell-Intrinsic Cholesterol Induces Lipid-Associated Macrophage Differentiation via SP1 Palmitoylation to Promote Prostate Cancer Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lactylation formation, gene regulation, biological functions, and clinical relevance.Histology and histopathology · 2026Review
- Review
- Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review).International journal of oncology · 2026Review
- Glyoxalase 2 Drives D-Lactate Oncometabolite Signaling to Promote Prostate Cancer Aggressiveness via FAK/Src Activation.Antioxidants (Basel, Switzerland) · 2026Article
- Lactylation in cancer: molecular mechanisms and advances in clinical study.Molecular cancer · 2026Review
- The interrelationship between prostate cancer and osteoporosis: new perspectives on shared molecular pathways and treatment strategies.International journal of surgery (London, England) · 2026Article
50 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
24 authors at 6 institutions in 2 countries.
Funding
Abstract
purposePhosphatase and tensin homolog (PTEN) loss of function occurs in approximately 50% of patients with metastatic castrate-resistant prostate cancer (mCRPC), and is associated with poor prognosis and responsiveness to standard-of-care therapies and immune checkpoint inhibitors. While PTEN loss of function hyperactivates PI3K signaling, combinatorial PI3K/AKT pathway and androgen deprivation therapy (ADT) has demonstrated limited anticancer efficacy in clinical trials. Here, we aimed to elucidate mechanism(s) of resistance to ADT/PI3K-AKT axis blockade, and to develop rational combinatorial strategies to effectively treat this molecular subset of mCRPC. EXPERIMENTAL
designProstate-specific PTEN/p53-deficient genetically engineered mice (GEM) with established 150-200 mm3 tumors, as assessed by ultrasound, were treated with either ADT (degarelix), PI3K inhibitor (copanlisib), or anti-PD-1 antibody (aPD-1), as single agents or their combinations, and tumors were monitored by MRI and harvested for immune, transcriptomic, and proteomic profiling, or ex vivo co-culture studies. Single-cell RNA sequencing on human mCRPC samples was performed using 10X Genomics platform.
resultsCoclinical trials in PTEN/p53-deficient GEM revealed that recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts ADT/PI3Ki combination-induced tumor control. The addition of aPD-1 to ADT/PI3Ki combination led to TAM-dependent approximately 3-fold increase in anticancer responses. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation within TAM, resulting in their anticancer phagocytic activation, which was augmented by ADT/aPD-1 treatment and abrogated by feedback activation of Wnt/β-catenin pathway. Single-cell RNA-sequencing analysis in mCRPC patient biopsy samples revealed a direct correlation between high glycolytic activity and TAM phagocytosis suppression.
conclusionsImmunometabolic strategies that reverse lactate and PD-1-mediated TAM immunosuppression, in combination with ADT, warrant further investigation in patients with PTEN-deficient mCRPC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.