Abstract: As a principal bioactive member of arsenic compounds, arsenic trioxide (ATO) is highly effective in treating hematologic malignancies, particularly acute promyelocytic leukemia (APL). Although ATO has strong tumoricidal activities in vitro, the clinical benefits of ATO monotherapy against solid tumors are often limited. Strategic exploration of novel ATO-based anti-cancer therapies have recently been promoted because of various drug combinations and targeted drug delivery approaches. However, breakthroughs in therapeutic outcomes have rarely been achieved. To that end, multiple mechanisms of action have been documented for ATO, including triggering reactive oxygen species generation, inhibiting the activity of glutathione peroxidase and several rate-limiting metabolic enzymes, causing oxidative stress, and initiating the mitochondrial apoptotic pathway. In particular, researches have long been focused on ATO cytotoxicity and the molecular mechanisms underlying ATO-induced cell death. However, whether ATO can boost tumor immunogenicity and influence anti-tumor immunity remains largely unknown. Therefore, we intend to summarize the current clinical applications of ATO, recapitulate its impacts on various cell death modalities, and analyze molecular associations among different cell death pathways. This review also preliminarily explores the possibility of whole-cell tumor vaccine development by maximizing ATO-triggered immunogenic cell death. Furthermore, the combination of immunotherapies with ATO-based tumor vaccine may provide novel possibilities for cancer treatment.