ArticleCellular & molecular immunology2024
The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation.
Article in Cellular & molecular immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 59 citations in OpenAlex.
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- An Avalanche Effect Nanomodulator Triggers Cascade Ferroptosis/Cuproptosis for Immunosuppressive Microenvironment Remodeling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Establishing human immune system mice: application, opportunity, and challenges.Experimental & molecular medicine · 2026Review
- FGFR4-high expression is associated with an immune-responsive phenotype in HCC and predicts inferior efficacy of lenvatinib plus PD-1 blockade.BMC cancer · 2026Article
- DAMP signaling networks: from receptors to diverse pathophysiological functions.Journal of advanced research · 2026Review
- Valrubicin-loaded immunoliposomes targeting antigens on immunosuppressive cells to circumvent resistance to cancer immunotherapy.Cell reports. Medicine · 2026Article
- Mitochondrial apoptosis gene-based pathomics for ovarian cancer prognosis.Scientific reports · 2026Article
- CTSB-positive tumor-associated macrophages shape prognosis and therapeutic response in lung adenocarcinoma.Translational oncology · 2026Article
- CAR-T triggers TAM reeducation and adaptive anti-tumor response via TREM2 deficiency or CD40 agonist.Cell reports. Medicine · 2026Article
- Targeting Tumor-Associated Macrophages to Reshape the Immuno-Mechanical Landscape: Molecular Mechanisms and Therapeutic Strategies.International journal of biological sciences · 2026Review
- p53 Orchestrates the Immunogenic-Tolerogenic Pyroptosis Switch in Non-Small Cell Lung Cancer: A Systems Biology Approach.Computational and structural biotechnology journal · 2026Article
- Innate immune signaling-driven myeloid remodeling in cancer: inflammatory amplification, immune suppression, and therapeutic targeting.Frontiers in immunology · 2026Review
- Lisaftoclax combined with ixazomib and dexamethasone after CAR-T for maintenance therapy in transplant-ineligible relapsed/refractory ultra-high-risk multiple myeloma: two case reports and literature review.Frontiers in oncology · 2026Article
- Inosine alleviates colorectal cancer liver metastasis by promoting M1 macrophage polarization and modulating the PI3K/AKT signaling pathway.Frontiers in immunology · 2026Article
- RICH1 enhances pro-inflammatory TAM infiltration in breast cancer via promoting TRIM21-mediated ubiquitination of RhoA and inhibiting STAT3 phosphorylation.NPJ precision oncology · 2025Article
- PD-1 Attenuates Neuropathic Pain by Ameliorating NLRP3 Inflammasome-Mediated Microglia Pyroptosis.Molecular neurobiology · 2025Article
- Lisaftoclax: First Approval.Drugs · 2025Review
- Microbial and Metabolic Disorders in Cervical Cancer: Structural Insights, Biomarkers, Mechanisms, and Therapeutic Strategies.Cancer science · 2025Review
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Authors and funding
20 authors at 1 institution in 1 country.
Funding
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Abstract
The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.
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