Background: Patients with cancer often experience clinically elevated levels of distress, including anxiety and depression. Psychological interventions, such as Cognitive Behavioral Stress Management (CBSM), have evidenced benefits on distress, quality of life, and long-term health outcomes, however, they are not widely available or easily accessible. Digitizing these interventions may be a means of democratizing access to cancer-focused and empirically-supported mental health care. Methods: This double-blind randomized controlled trial (RCT) compared the impact of a 10-module digitized CBSM app [attune] vs. a health education control app [cerena] on anxiety and depression symptoms in patients with cancer (n=449). Patients with non-metastatic (stage I-III) and hematological cancers who were receiving or recently (≤6 months) completed systemic treatment and reported a PROMIS-A T-Score >60 were recruited to participate in this decentralized clinical trial through a nationwide online advertising campaign. The pre-specified primary outcome was change in anxiety symptoms (PROMIS-A) across conditions over time (week 0, 4, 8, and 12) in the intention-to-treat population analyzed using a linear mixed effects model with repeated measures. Secondary outcomes included change in depression symptoms (PROMIS-D) and global impression of change in anxiety and depression (PGI-C). Results: Patients in the study were 80.6% female, 76.5% white, and the mean (SD; range) age was 52.44 (11.46; 25-80) years. Compared to the control, attune participants showed significantly greater reductions in anxiety (β=-0.03; p=0.019) and depression (β=-0.02; p=0.042) symptoms over 12-weeks, and at end-of-study (week 12) there was a greater proportion of attune participants in the PROMIS-A (χ²=7.13; p=0.004) and PROMIS-D (χ²=3.53; p=0.035) mild-none symptom severity category. There were also significant group differences in PGI-C, with attune participants more likely to report ‘much’ or ‘very much’ improvement in their anxiety (χ²=31.76; p<0.001) and depression symptoms (χ²=19.70; p<0.001). Conclusions: Digital therapeutics have the potential to improve access to empirically supported psychological treatments for symptoms of anxiety and depression in patients with cancer. In this decentralized, double-blind RCT, we show that compared with a visually and functionally similar sham app, patients who used attune had significantly greater reductions in anxiety and depression symptoms over time. Moreover, at the end of the study, participants who used attune were significantly more likely to report their anxiety and depression symptoms were ‘much’ or ‘very much’ improved, indicating clinically meaningful change. Future work aims to explore implementation strategies to maximize benefit and accessibility of this cancer-specific digital therapeutic. Clinical trial information: NCT05227898.