Embryonic germ layer origin fundamentally shapes cancer therapy response patterns, with mesoderm-derived malignancies showing responsiveness to cellular immunotherapy, endoderm-derived epithelial cancers demonstrating sensitivity to protein signaling inhibitors, and ectoderm-derived tumors exhibiting immunogenicity enabling breakthrough responses to checkpoint blockade and mRNA vaccine strategies. To investigate these patterns, we conducted a systematic review, using a guided review method and large language learning models, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 guidelines, and searched PubMed, Embase, and Web of Science through October 2025. Evidence synthesis incorporated National Comprehensive Cancer Network Clinical Practice Guidelines, American Society of Clinical Oncology publications, American Cancer Society statistics, and landmark Phase 3 and Phase 4 clinical trials. Given extreme clinical heterogeneity, we performed narrative synthesis with megatrend analysis, employing triple-checking verification methodology of all clinical outcome data using independent search strategies, with explicit documentation of large language model-assisted abstract screening followed by an exclusive human reviewer completion of eligibility assessment, data extraction, and synthesis. Three major megatrends emerged from our analysis: mesoderm-derived hematologic malignancies achieved relevant response rates of 82–97% with chimeric antigen receptor T-cell therapies across multiple pivotal trials; endoderm-derived adenocarcinomas demonstrated vulnerability to targeted therapies, with median overall survival extending to 19–47 months with matched protein pathway inhibitors; and ectoderm-derived melanoma showed immune control with checkpoint blockade achieving approximately 34% 10-year overall survival and 49% risk reduction with personalized mRNA neoantigen vaccines. These findings suggest that embryonic lineage provides a potentially valuable exploratory context for understanding therapeutic response patterns, complementing molecular biomarker-driven precision oncology to guide treatment selection, trial design, and drug development prioritization.