Heat has been used as an anti-tumor therapy for centuries. One such treatment, mild temperature hyperthermia, does not directly eradicate tumors but sensitizes them to other treatments like radiotherapy. Despite growing evidence of its effectiveness, clinicians often avoid the approach because the methods to attain, maintain, and monitor hyperthermia are unwieldy and invasive.1 To get around these problems, we have developed a strategy combining optically activated nanoparticles and magnetic resonance imaging (MRI) to noninvasively induce and monitor mild temperature hyperthermia. Nanoshells (∼150nm) with a silica core and a gold shell are biologically inert and can be optically activated. By varying the ratio of core size to shell thickness, they can be tuned to maximally absorb and convert near infrared (NIR) light to heat. NIR light has the most clinical utility because its low attenuation allows for deeper penetration of tissue. When administered intravenously, the nanoshells easily leak through immature tumor blood vessels to accumulate preferentially within the growths. The particles accumulate passively, then generate heat uponNIR illumination. First, we demonstrated that we could noninvasively and reproducibly achieve mild temperature hyperthermia. We directly inserted thermocouples into the center and base of nanoshellfilled colorectal cancers that were artificially created on mouse thighs. Next, we established optimal laser parameters with gradual elevation of core tumor temperature to mild hyperthermia levels (∼41◦C) for ∼20min. These direct measurements were reconfirmed using MRI thermometry, a real-time noninvasive means of monitoring hyperthermia (see Figure 1). Next, we evaluated the time to tumor volume doubling in mice treated with radiotherapy—both with and without hyperthermia immediately preceding it. Tumors took nearly twice as long to double in volume after combined treatment as compared to radiotherapy alone. We wanted to understand the enhanced efficacy of combined therapy, given that mild temperature increases alone do not kill cancer cells. Therefore, we first looked at hyperthermia’s effect on blood flow to the growths. Dynamic contrast enhancedMRI (DCE-MRI) showed that immediately after raising temperatures (<5min), blood flow to the core of the tumor significantly increased. This higher flow of blood oxygenated the tumor’s central regions that are normally deficient in oxygen (see Figure 2). Reducing the number of these hypoxic cells (which have a three-fold greater resistance to radiotherapy than normoxic cells) makes tumors more sensitive to the treatment. To further understand radiosensitization, we treated separate cohorts of mice with hyperthermia, radiotherapy, both, or neither and extracted tumors 90 minutes after treatment. Just