Personalized nanovaccines from tumor cells: reshaping the microenvironment and defeating heterogeneity

Abstract

Tumor heterogeneity and an immunosuppressive microenvironment are major obstacles to effective cancer immunotherapy. Personalized nanovaccines derived from autologous tumor cells offer a compelling strategy to overcome these challenges by preserving the full spectrum of patient-specific neoantigens without requiring individual identification of neoantigens. This review systematically categorizes four major platforms: tumor cell lysate-based nanovaccines, tumor cell membrane-coated nanoparticles (NPs), tumor-derived extracellular vesicles (EVs), and in situ nanovaccines. We discuss advanced bioengineering strategies that enhance antigen presentation through valency control, nanoscale spatial patterning, and shape-dependent lymph node trafficking. We further highlight artificial intelligence as an enabling design pillar for neoantigen prioritization, NP formulation optimization, stimuli-responsive carrier design, and patient stratification. Specific nanovaccine platforms, including self-emulsifying, self-aggregating, logic-gated, and nanorobot systems, are highlighted, along with key mechanisms for reshaping the tumor microenvironment (TME), such as physical barrier disruption, metabolic reprogramming, and modulation of critical signaling pathways. The induction of ICD and its variants, pyroptosis, ferroptosis, and cuproptosis, has also been explored as an in-situ vaccination strategy. While no autologous tumor cell-derived nanovaccine has yet received FDA approval, the clinical success of personalized mRNA vaccines (BNT122, mRNA-4157, LK101), a KRAS neoantigen bacterial membrane nanovaccine, the erythrocyte–anti-PD1 conjugate (αPD1-Ery), the TNBC-MERIT study with six-year relapse-free survival (10 out of 14), and methotrexate-loaded tumor-derived exosome nanovaccines for cholangiocarcinoma provides a regulatory roadmap. Preclinical platforms, including PLGA/R848-based M1 macrophage membrane nanovaccines, are advancing toward clinical applications. Despite challenges in manufacturing standardization, off-target autoimmunity, and long-term regulatory safety, autologous tumor cell-derived nanovaccines represent a promising paradigm for potentially durable tumor-specific immunity, particularly for preventing postoperative recurrence and metastasis in high-risk cancer patients.