Beyond the Generic Tumor: Engineering Patient-Specific Immune Ecosystems for Cancer.

Abstract

Cancer immunotherapy has transformed the treatment landscape of malignancies; however, durable clinical responses remain limited by interpatient heterogeneity, tumor evolution, antigen loss, and variability in immune recognition. Advances in genomic sequencing, neoantigen discovery, immunopeptidomics, mRNA-based therapeutics, and cellular engineering have expanded opportunities for developing individualized immunotherapeutic strategies based on patient-specific tumor and immune characteristics. This review examines the state of personalized cancer immunotherapy, with emphasis on individualized neoantigen-specific therapies (iNeST), neoantigen vaccines, mRNA-based antigen delivery platforms, engineered T-cell approaches, and computational methods for antigen prioritization and immune-response prediction. We summarize the biological rationale, preclinical and clinical evidence, and limitations of these approaches, while considering their translational potential and clinical feasibility. We examine the relationships among tumor mutational landscapes, neoantigen immunogenicity, antigen processing and presentation, HLA restriction, immune-cell engineering, and computational immunology. We further assess key barriers to clinical implementation, including limitations in neoantigen prediction and validation, intratumoral heterogeneity, antigen evolution and loss, manufacturing complexity, scalability, regulatory requirements, and the need for prospective clinical validation. Overall, current evidence supports personalized immunotherapy as a promising approach for improving the precision of cancer treatment, but its clinical application remains constrained by biological, technical, manufacturing, regulatory, and clinical challenges. Future progress will require more accurate and experimentally validated neoantigen identification, improved computational and immunologic modeling, robust manufacturing and quality-control processes, and prospective clinical studies demonstrating safety, feasibility, and therapeutic benefit. This review evaluates the current evidence, identifies knowledge gaps, and outlines priorities for the responsible clinical development of individualized cancer immunotherapy.