{"doi":"10.1101/2025.08.22.671875","title":"A Transient Immunostimulatory Niche Synergizes Adoptive and Endogenous Immunity for Enhanced Tumor Control","abstract":"Abstract Adoptive Cell Therapy (ACT) has achieved curative responses in hematological malignancies, yet its translation to solid tumors remains limited by manufacturing bottlenecks, systemic toxicities, and poor T-cell infiltration and persistence within the immunosuppressive tumor microenvironment (TME). Here, we report the development and mechanism of ACTIVATE (Adoptive Cell Therapy and Immunostimulatory Vehicle for Anti-Tumor Efficacy), which leverages an injectable hydrogel depot technology that forms a transient inflammatory niche for localized co-delivery of adoptive T cells and native cytokines. By tuning cytokine identity, ACTIVATE enables precise modulation of T-cell expansion, effector function, and interaction with endogenous immune networks. We found that enhancing T-cell proliferation alone is insufficient to drive robust tumor control; instead, coordinated engagement of both adoptive and endogenous immune responses is critical for durable anti-tumor efficacy. In vivo , this orchestration via ACTIVATE led to enhanced infiltration and cytotoxicity of both adoptive and host-derived immune effectors, while driving robust recruitment and activation of T cells, B cells, dendritic cells, and macrophages in the tumor-draining lymph nodes. This local immune activation can further reshape the TME, promoting antigen presentation and suppressing immunoregulatory populations, thus enhancing anti-tumor efficacy in murine melanoma and lymphoma models. These findings establish ACTIVATE as a modular platform for orchestrating coordinated immune responses to improve ACT outcomes in solid tumors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558881,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"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":808304,"name":"John H. Klich","orcid":"0000-0002-9285-1018","position":1,"is_corresponding":false},{"id":1089706,"name":"Noah Eckman","orcid":"0000-0002-4183-0153","position":2,"is_corresponding":false},{"id":1379997,"name":"Sophia J. Bailey","orcid":"0000-0001-6477-8936","position":3,"is_corresponding":false},{"id":1459666,"name":"Karine Gillard","orcid":"0000-0002-3340-4410","position":4,"is_corresponding":false},{"id":1044418,"name":"Daniel Ramos Mejia","orcid":"0009-0003-5374-3289","position":5,"is_corresponding":false},{"id":635907,"name":"Ben S. Ou","orcid":"0000-0002-0539-5166","position":6,"is_corresponding":false},{"id":259695,"name":"Jerry Yan","orcid":"0000-0001-8278-1354","position":7,"is_corresponding":false},{"id":615289,"name":"John W. Hickey","orcid":"0000-0001-9961-7673","position":8,"is_corresponding":false},{"id":278141,"name":"Eric A. Appel","orcid":"0000-0002-2301-7126","position":9,"is_corresponding":false},{"id":506513,"name":"Anahita Nejatfard","orcid":"0000-0001-6242-2506","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40909524","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":[]}