{"doi":"10.1007/s00262-025-04096-y","title":"Cell-specific nanoengineering strategy to disrupt tolerogenic signaling from myeloid-derived suppressor cells and invigorate antitumor immunity in pancreatic cancer","abstract":"Pancreatic ductal adenocarcinoma (PDAC) is characterized by intratumoral abundance of neutrophilic/polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) which exert anti-T-cell functions through multiple mechanisms, especially JAK2/STAT3-regulated arginase activity. To overcome limitations of systemic inhibition of PMN-MDSCs in cancer-bearing patients such as neutropenia and compensatory myelopoietic adaptations, we developed a nanoengineering strategy to disrupt cell-specific signaling exclusively in PMN-MDSCs without compromising viability or provoking neutropenia. Single-cell RNA sequencing in human/murine PDAC, and flow cytometry in peripheral blood cells from treatment-naïve PDAC patients, nominated surface receptor CXCR2 as a PMN-MDSC-exclusive target. We chemically modified a small-molecule CXCR2 inhibitor AZD5069 by conjugating it with polyethylene glycol (PEG) to enhance aqueous solubility. This AZD5069-PEG construct was then chemically grafted onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Cy5.5 dye-loaded CXCR2-NPs showed near-exclusive uptake in PMN-MDSCs compared with Kras LSL.G12D/ + ;p53 R172H/ + ;Pdx1 Cre/ + (KPC) PDAC tumor cells, KPC cancer-associated fibroblasts, macrophages, and dendritic cells. Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NP Ruxo ) resulted in more efficient and durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs as well as robust induction of cytolytic T-cell activity compared with free Ruxolitinib in vitro and in orthotopic tumor cell-CAF co-injection models in vivo. Treatment of orthotopic tumor-bearing KPC mice with CXCR2-NP Ruxo reduced tumor burden compared with vehicle, free Ruxolitinib, or non-drug-loaded CXCR2-NP treatments, without causing appreciable neutropenia. Taken together, cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC.","journal":"Cancer Immunology Immunotherapy","year":2025,"id":531546,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":315593,"name":"Anna Bianchi","orcid":"0000-0002-5963-103X","position":1,"is_corresponding":false},{"id":1018168,"name":"Haleh Amirian","orcid":"0000-0002-6094-1342","position":2,"is_corresponding":false},{"id":661635,"name":"Iago De Castro Silva","orcid":"0000-0002-3898-6173","position":3,"is_corresponding":false},{"id":369311,"name":"Christine I. Rafie","orcid":"0000-0002-2917-7016","position":4,"is_corresponding":false},{"id":678968,"name":"Bapurao Surnar","orcid":"0000-0001-5997-3120","position":5,"is_corresponding":false},{"id":1194730,"name":"Karthik Rajkumar","orcid":"0000-0002-3604-3657","position":6,"is_corresponding":false},{"id":1058555,"name":"Akash Ashokan","orcid":"0000-0003-3626-2814","position":7,"is_corresponding":false},{"id":913582,"name":"Ifeanyichukwu C. Ogobuiro","orcid":"0000-0002-1094-6727","position":8,"is_corresponding":false},{"id":1388997,"name":"Manan Patel","orcid":"0000-0001-6978-960X","position":9,"is_corresponding":false},{"id":622420,"name":"Erietta Stelekati","orcid":null,"position":10,"is_corresponding":false},{"id":678974,"name":"Shanta Dhar","orcid":"0000-0003-3042-5272","position":11,"is_corresponding":false},{"id":661636,"name":"Jashodeep Datta","orcid":"0000-0002-5052-7586","position":12,"is_corresponding":false},{"id":643008,"name":"Nilesh Deshpande","orcid":"0000-0002-3912-089X","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":null,"created_at":"2026-07-19T02:51:14.579161Z","pmid":"40549154","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}