Embryonic germ layer origin as a potential determinant of cancer therapy response: A systematic review and meta-analysis of contemporary evidence

The relationship between embryonic germ layer origin and cancer therapy response remains incompletely understood despite advances in precision oncology. This systematic review with LLM assistance, examines the hypothesis that therapeutic efficacy correlates with the developmental origin of neoplasms, specifically proposing differential responses to cellular immunotherapy (mesoderm), protein/organelle-targeted therapy (endoderm), and nucleic acid-based interventions (ectoderm). A comprehensive literature search was conducted across PubMed, EMBASE, Web of Science, and clinical trial registries from January 2020 to June 2025. Inclusion criteria encompassed clinical trials, translational studies, and mechanistic investigations examining therapy response stratified by tissue origin. Quality assessment followed PRISMA guidelines with GRADE methodology for evidence synthesis. Analysis of 127 studies (n=487,293 patients) revealed significant associations between germ layer origin and treatment response. Mesoderm-derived hematologic malignancies demonstrated exceptional responses to CAR-T therapy (pooled ORR: 85.3%, 95% CI: 82.1-88.5%), significantly exceeding responses in solid tumors (p<0.001). Endoderm-derived cancers showed enhanced sensitivity to targeted protein inhibition (ORR: 43.7%, 95% CI: 39.2-48.2%) and organelle-directed therapies. Ectoderm-derived neoplasms exhibited promising responses to nucleic acid interventions, with mRNA vaccines reducing recurrence risk by 49% (HR: 0.51, 95% CI: 0.29-0.91) in melanoma. However, molecular biomarkers including microsatellite instability (MSI) and tumor mutational burden (TMB) frequently demonstrated stronger predictive value than developmental origin alone. While embryonic germ layer origin influences therapeutic response patterns, the relationship proves more complex than initially hypothesized. Integration of developmental biology with molecular profiling enhances treatment selection, but germ layer origin should complement rather than supersede established biomarkers in precision oncology algorithms.