{"doi":"10.1073/pnas.2107507118","title":"Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells","abstract":"Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dual-specific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site-specific activity in the tissue, and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising NK cell-based combinatorial strategy that can target multiple clinically recognized mechanisms of GBM progression simultaneously.","journal":"Proceedings of the National Academy of Sciences","year":2021,"id":150626,"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":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":569258,"name":"Sandra Toregrosa-Allen","orcid":null,"position":1,"is_corresponding":false},{"id":303989,"name":"Bennett D. Elzey","orcid":"0000-0002-6658-7970","position":2,"is_corresponding":false},{"id":303986,"name":"Sagar M. Utturkar","orcid":"0000-0002-3453-1948","position":3,"is_corresponding":false},{"id":338751,"name":"Nadia A. Lanman","orcid":"0000-0002-1819-7070","position":4,"is_corresponding":false},{"id":283168,"name":"Victor Bernal-Crespo","orcid":"0000-0002-7161-3600","position":5,"is_corresponding":false},{"id":568332,"name":"Matthew M. Behymer","orcid":"0000-0002-5856-6360","position":6,"is_corresponding":false},{"id":452821,"name":"Gregory T. Knipp","orcid":"0000-0002-4199-2929","position":7,"is_corresponding":false},{"id":568333,"name":"Yeonhee Yun","orcid":"0009-0008-9676-3630","position":8,"is_corresponding":false},{"id":568334,"name":"Michael C. Veronesi","orcid":"0000-0001-8551-151X","position":9,"is_corresponding":false},{"id":327572,"name":"Anthony L. Sinn","orcid":null,"position":10,"is_corresponding":false},{"id":326016,"name":"Karen E. Pollok","orcid":"0000-0001-6031-5707","position":11,"is_corresponding":false},{"id":378955,"name":"Randy R. Brutkiewicz","orcid":"0000-0002-7396-480X","position":12,"is_corresponding":false},{"id":568335,"name":"Kathryn Nevel","orcid":"0000-0003-1499-837X","position":13,"is_corresponding":false},{"id":351553,"name":"Sandro Matosevic","orcid":"0000-0001-5118-2455","position":14,"is_corresponding":false},{"id":351552,"name":"Jiao Wang","orcid":"0000-0001-6718-8333","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:43:06.501849Z","pmid":"34740973","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":[]}