Enhancing whole tumor cell-based cancer vaccines using nanotechnology: from historical limitations to next-generation immunotherapeutic platforms

Whole tumor cell (WTC)-based cancer vaccines offer an attractive immunotherapeutic strategy by providing a comprehensive and patient-relevant cancer antigen repertoire capable of addressing tumor heterogeneity and antigenic escape. However, early clinical and preclinical efforts using unmodified WTC lysates yielded limited efficacy, largely due to inadequate immunogenic context, inefficient antigen processing, and suboptimal antigen presentation. In recent years, advances in nanotechnology have driven a paradigm shift in WTC-based vaccine design, transforming these formulations from passive antigen sources into programmable immunotherapeutic platforms. This review critically examines the evolution of WTC-based nanovaccines, discussing emerging antigen engineering strategies that actively modulate antigen quality and intracellular fate, including tumor cell stress conditioning, proteasomal routing control, and the exploitation of autophagy-derived antigen reservoirs to enhance antigen cross-presentation. In parallel, hybrid and biomimetic nanoplatforms are reviewed as approaches that integrate physiological cues governing antigen topology, innate immune sensing, lymphoid trafficking, and antigen presenting cell–T cell communication. Finally, we summarize recent advances in therapeutic combinatory strategies and translationally relevant models, underscoring the growing clinical relevance of WTC-based nanovaccines.