Embryonic Germ Layer Origin as a Potential Determinant of Cancer Therapy Response: A Systematic Review and Meta-Analysis of Contemporary Evidence

BackgroundCancer therapeutic response patterns may be fundamentally influenced by embryonic germ layer origin. Emerging evidence suggests mesoderm-derived malignancies exhibit exceptional responsiveness to cellular immunotherapy, endoderm-derived epithelial cancers demonstrate marked sensitivity to protein signaling inhibitors, and ectoderm-derived tumors show heightened immunogenicity enabling breakthrough responses to checkpoint blockade and messenger RNA vaccine strategies. MethodsWe conducted a systematic review following PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, and Web of Science were searched from inception through 13 October 2025 using predefined PICOS criteria and a reproducible search strategy. A prespecified protocol (archived; no prior registry) guided screening, data extraction, and risk-of-bias assessment. EligibilityWe included patients with malignancies assignable to ectoderm, mesoderm, or endoderm lineages receiving cellular immunotherapies, protein-targeted agents/antibody-drug conjugates, or nucleic acid/immunomodulatory therapies. Eligible comparators included active controls, standard care, placebo, or single-arm designs where appropriate. Study designs comprised randomized controlled trials, non-randomized comparative studies, and pivotal single-arm trials in refractory settings. We excluded preclinical studies, case reports/series with fewer than ten patients, studies without extractable endpoints, duplicate/superseded publications, and cancers with unassignable lineage. Outcomes and AnalysisPrimary outcomes were objective response rate, progression-free survival, and overall survival. Secondary outcomes included complete response, duration of response, event-free/recurrence-free survival, and safety. Effect measures were hazard ratios for time-to-event data and risk/odds ratios for binary outcomes. Random-effects meta-analysis was planned for clinically and statistically homogeneous subsets; otherwise, we performed SWiM-compliant narrative synthesis with megatrend analysis given extreme clinical heterogeneity. Evidence synthesis incorporated National Comprehensive Cancer Network Clinical Practice Guidelines, American Society of Clinical Oncology publications, American Cancer Society statistics, and landmark phase III/IV clinical trials. VerificationClinical outcome data underwent triple-checking using independent search strategies. Large language model tools assisted with abstract screening prioritization only; all eligibility assessment, data extraction, risk-of-bias evaluation, and synthesis were performed exclusively by human reviewers. FindingsThree major megatrends emerged. First, mesoderm-derived hematologic malignancies achieved complete response rates of 82-97% with chimeric antigen receptor T-cell therapies across multiple pivotal trials. Second, endoderm-derived adenocarcinomas demonstrated consistent vulnerability to targeted therapies, with median overall survival of 19-47 months when treated with matched protein pathway inhibitors. Third, ectoderm-derived melanoma exhibited sustained immune control, with checkpoint blockade achieving 43% ten-year overall survival in advanced disease and personalized messenger RNA neoantigen vaccines providing 49% risk reduction for recurrence in the adjuvant setting. InterpretationEmbryonic germ layer origin provides valuable exploratory context for understanding cancer therapeutic response patterns. This developmental framework complements molecular biomarker-driven precision oncology and may inform treatment selection, clinical trial design, and drug development prioritization.