Abstract Conventional cancer therapies emphasize eradication, often at the expense of harming healthy tissue and immune compromise. This article explores a paradigm-shifting concept: repurposing tumor cells not merely as targets, but as active therapeutic agents. By harnessing their self-homing ability, antigen diversity, and adaptive survival mechanisms, these engineered tumor cells can be repurposed to deliver therapeutic payloads, remodel the tumor microenvironment, and even function as antigen-presenting cells. We begin by critically analyzing the mechanistic failures of early whole-cell vaccine approaches, highlighting how their limited efficacy stemmed from underestimating both the tumor’s potent adaptive resistance and the deeply immunosuppressive nature of its microenvironment. We then discuss next-generation strategies designed to overcome these hurdles, with approaches ranging from “killer vaccines” and APC-like reprogramming to Trojan horse delivery of oncolytic viruses. The translational challenges, ranging from multi-layered safety engineering, GMP manufacturing, regulatory navigation, patient selection, and ethical considerations, are examined in depth, with key insights drawn from the clinical evolution of CAR-T cell therapy. We conclude by outlining a clinical roadmap and rational combinatorial strategies, proposing that if these barriers are overcome, tumor cell-based therapies could emerge as complements to immune checkpoint inhibitors and adoptive cell therapies, thus transforming the tumor from an adversary into a catalyst of its own defeat.
Chen et al. (Fri,) studied this question.