{"doi":"10.3389/fimmu.2025.1698158","title":"Synthetic biology approaches to enhance cancer immune responses","abstract":"<jats:p>Synthetic biology is being widely applied in tumor therapy, ranging from attenuating microbial toxicity to constructing synthetic gene circuits and developing CAR-T cells, all of which are reshaping the landscape of cancer immunotherapy. In this review, we summarize recent advances in microbial-based therapeutics that leverage bacteria’s natural tropism for hypoxic tumor regions to deliver immunomodulatory payloads with high spatial precision. Parallel progress in CAR-T cell engineering has led to the development of armored and logic-gated constructs designed to overcome challenges such as antigen heterogeneity, the immunosuppressive tumor microenvironment, and T cell exhaustion. Synthetic biology further integrates these platforms via programmable genetic circuits capable of performing Boolean logic operations, ensuring therapeutic activation only in the presence of tumor-specific biomarkers. While this convergence offers the unprecedented precision, safety, and potency in reprogramming anti-tumor immunity, the clinical translation of these complex systems faces significant hurdles. Despite challenges in clinical translation-including safety concerns, immune clearance, and manufacturing complexity-the field is advancing toward multifunctional “smart” therapies, synergistic microbial-cell combinations, and personalized treatment strategies. Together, these innovations are defining a new generation of precision-engineered immunotherapies with the potential to transform the treatment of refractory malignancies.</jats:p>","journal":"Frontiers in Immunology","year":2025,"id":649417,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"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":1692929,"name":"Zhihao Zhong","orcid":null,"position":1,"is_corresponding":false},{"id":1692930,"name":"Qihang Tu","orcid":null,"position":2,"is_corresponding":false},{"id":1454751,"name":"Meiling Jin","orcid":"0000-0002-0093-0377","position":3,"is_corresponding":false},{"id":1366984,"name":"Shuzhen Liu","orcid":"0000-0002-0602-3217","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Synthetic biology approaches to enhance cancer immune responses","abstract":"<jats:p>Synthetic biology is being widely applied in tumor therapy, ranging from attenuating microbial toxicity to constructing synthetic gene circuits and developing CAR-T cells, all of which are reshaping the landscape of cancer immunotherapy. In this review, we summarize recent advances in microbial-based therapeutics that leverage bacteria’s natural tropism for hypoxic tumor regions to deliver immunomodulatory payloads with high spatial precision. Parallel progress in CAR-T cell engineering has led to the development of armored and logic-gated constructs designed to overcome challenges such as antigen heterogeneity, the immunosuppressive tumor microenvironment, and T cell exhaustion. Synthetic biology further integrates these platforms via programmable genetic circuits capable of performing Boolean logic operations, ensuring therapeutic activation only in the presence of tumor-specific biomarkers. While this convergence offers the unprecedented precision, safety, and potency in reprogramming anti-tumor immunity, the clinical translation of these complex systems faces significant hurdles. Despite challenges in clinical translation-including safety concerns, immune clearance, and manufacturing complexity-the field is advancing toward multifunctional “smart” therapies, synergistic microbial-cell combinations, and personalized treatment strategies. Together, these innovations are defining a new generation of precision-engineered immunotherapies with the potential to transform the treatment of refractory malignancies.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41394856","pmcid":"PMC12695825","openalex_id":null,"authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":null,"license":"https://creativecommons.org/licenses/by/4.0/","oa_locations":[{"url":"https://www.frontiersin.org/articles/10.3389/fimmu.2025.1698158/full","host_type":"publisher"},{"url":"https://europepmc.org/articles/PMC12695825","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12695825?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":[],"mesh_terms":["Animals","Humans","Neoplasms","Immunotherapy","Immunotherapy, Adoptive","Synthetic Biology","Tumor Microenvironment","Receptors, Chimeric Antigen"],"keywords":["Engineered bacteria","Cancer Immunotherapy","Synthetic Biology","Synthetic Gene Circuits","Car-t Cells"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T03:40:38.884702Z","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":[]}