Abstract Hepatocellular carcinoma is a lethal disease and the fastest growing type of cancer in the United States. Most patients are not candidates for surgery and medical therapy has only recently achieved a limited survival benefit of 2-3 months with sorafenib. This drug is costly and has a number of side effects limiting its acceptance and impact. Locoregional therapies treating tumor in situ likewise have limitations, although the survival benefit is generally longer. Major clinical weaknesses of existing therapies such as ablation and embolization are incomplete treatment and local recurrence. In the current proposal, we seek to harness the exothermic chemical reaction between an acid and a base to release heat and a salt at high local concentration to kill tumor tissue. We hypothesize that the combination of simultaneous thermal and osmotic stress is highly effective in killing tumor cells and that the process can be imaged and controlled. In the first aim we propose to perform MRI temperature imaging to map the thermal dose, combined with multi-gradient echo recall chemical shift imaging to map the salt with high temporal resolution, and sodium MRI to map the concentration of the sodium in the treated volume. In the second aim we will perform in vitro experiments on tumor cell lines to understand how cells respond to this kind of combined stress and interrogate likely pathways for future intervention. In the final aim we propose to test the concept in vivo using the rabbit VX2 tumor model, which is large enough to allow for the thermal and sodium imaging.