Engineering whole tumor cell vaccines for cancer immunotherapy: From malignant cells to therapeutic vaccines.

Tumor cells are the driving force of cancer progression, yet they also constitute a rich reservoir of tumor-associated and patient-specific antigens that can be harnessed for therapeutic vaccination. Whole tumor cell vaccines (WTCVs) exploit this unique duality by converting malignant cells into immunotherapeutic agents capable of eliciting broad antitumor immunity and overcoming tumor heterogeneity. However, their clinical translation remains constrained by the need to eliminate tumorigenic potential while preserving or enhancing immunogenicity. Here, we provide a comprehensive overview of recent advances in the engineering of WTCVs from the perspectives of safety assurance and therapeutic enhancement. We summarize current strategies for controlling tumorigenicity, including physical, chemical, engineered, and viability-preserving approaches, and discuss emerging immunopotentiation strategies that enhance antigen abundance and exposure, improve antigen presentation, activate innate and adaptive immune pathways, and integrate complementary therapeutic modalities. Collectively, these advances are transforming malignant cells into multifunctional therapeutic vaccines capable of eliciting potent and durable antitumor immunity. Finally, we discuss the key challenges and future opportunities for next-generation WTCVs and highlight design principles that may accelerate their clinical translation.