{"doi":"10.3390/ijms26199554","title":"Overcoming Immune Therapy Resistance in Cancer Through Innate Immune Reprogramming","abstract":"<jats:p>Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic cells, restoring antigen presentation, and recruiting effector T and NK cells. In this review, we synthesize mechanistic insights into how these receptors function across tumor and immune compartments and evaluate recent translational advances spanning small-molecule and nucleic acid agonists, engineered delivery systems, and clinical trials. We highlight challenges that have limited clinical impact, including pathway silencing, systemic toxicity, and lack of predictive biomarkers, while emphasizing emerging solutions such as tumor-intrinsic targeting, CAR-T/NK engineering, and biomarker-guided patient selection. By integrating innate activation into rational combination regimens, innate immune reprogramming offers a blueprint to convert resistant disease into one susceptible to durable immune control.</jats:p>","journal":"International Journal of Molecular Sciences","year":2025,"id":622193,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1607477,"name":"Nardine Soliman","orcid":"0009-0002-8577-5333","position":1,"is_corresponding":false},{"id":1226254,"name":"Nadia El Khawanky","orcid":"0000-0001-8133-5061","position":2,"is_corresponding":false},{"id":1607476,"name":"Giada Mandracci","orcid":"0009-0006-4805-6988","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Overcoming Immune Therapy Resistance in Cancer Through Innate Immune Reprogramming","abstract":"<jats:p>Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic cells, restoring antigen presentation, and recruiting effector T and NK cells. In this review, we synthesize mechanistic insights into how these receptors function across tumor and immune compartments and evaluate recent translational advances spanning small-molecule and nucleic acid agonists, engineered delivery systems, and clinical trials. We highlight challenges that have limited clinical impact, including pathway silencing, systemic toxicity, and lack of predictive biomarkers, while emphasizing emerging solutions such as tumor-intrinsic targeting, CAR-T/NK engineering, and biomarker-guided patient selection. By integrating innate activation into rational combination regimens, innate immune reprogramming offers a blueprint to convert resistant disease into one susceptible to durable immune control.</jats:p>","is_dataset_classified":null,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41096817","pmcid":"PMC12525178","openalex_id":"https://openalex.org/W4414652658","authors":[],"funders":[],"total_grants":0,"fwci":4.0206,"citation_percentile":0.9472471,"influential_citations":0,"citation_trend":[{"year":2025,"count":1},{"year":2026,"count":9}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/26/19/9554/pdf?version=1759225112","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/26/19/9554/pdf?version=1759225112","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/26/19/9554/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms26199554","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41096817","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12525178","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12525178","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12525178?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Immune Cell Function and Interaction","interferon and immune responses","Immune cells in cancer"],"mesh_terms":["Animals","Humans","Immunity, Innate","Immunotherapy","Killer Cells, Natural","Neoplasms","Drug Resistance, Neoplasm","Tumor Microenvironment"],"keywords":["Innate immune system","Reprogramming","Immune system","Immunotherapy","Innate lymphoid cell","Effector","Cancer immunotherapy","Pattern recognition receptor","Dendritic cells","TLRs","innate immunity","RIG-I","MDA5","Tumor Microenvironment","Pattern Recognition Receptors","Nucleic Acid Sensing","Immune Therapy Resistance","Sting Pathway"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T18:36:05.397785Z","pmid":null,"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":[]}