Abstract Accurate dose delivery at the tumor site is crucial for the success of radiotherapy (RT) for cancer treatment. However, as yet there are no techniques in clinics with the ability to monitor RT. This project proposes X-ray- induced acoustic (XA) computed tomography (XACT) to facilitate dose monitoring during RT. Pulsed X-ray radiation, when absorbed by tissues, leads to thermoelastic expansion which generates acoustic waves. These waves can be sensed by ultrasonic transducers around the irradiated tissue and fed to an XACT algorithm to reconstruct the X-ray energy deposition (XED) maps. As an expert in computational biomedical imaging, Dr. Pandey’s current challenge is to develop efficient XACT algorithms to enable real-time/near real-time quantitative monitoring of the XED: the focus of the proposed project. Existing RT setups in clinics only need to integrate a transducer array to adopt XACT-based radiation dosimetry without significantly affecting existing RT practices. Dr. Pandey is key personnel in the ongoing projects funded by the NIH/NCI (R37 CA240806) and the American Cancer Society (133697-RSG-19-110-01-CCE); Dr. Liangzhong Xiang is the Principal Investigator. These projects aim to achieve in vivo dosimetry using XACT. Although XACT has seen substantial utilization in dosimetry research, certain challenges hinder its clinical translation. The first one being suboptimal signal-to-noise ratios (SNR) in XA signals and the main focus of Dr. Xiang’s R37 research is towards developing advanced instrumentation to resolve this. Dr. Pandey’s research as well as this R50 proposal addresses the algorithmic challenges which include the limited view artifacts, absence of quantitative dose information, and lack of the capability of correcting for acoustic heterogeneity in the reconstructed dose maps. The key objectives of this proposal are coherent with the aims of the ongoing NCI and ACS projects. Protons, owing to their unique energy deposition characteristics, are an attractive choice for RT. Much like X- rays, clinical pulsed proton beams are also known to produce acoustic waves and Dr. Xiang’s group’s recent preliminary studies (with Dr. Pandey’s contribution) have shown the capability of dose monitoring during proton therapy which led to the NIH/NCI U01 Award (U01CA288351). Since XA and proton-induced acoustic waves share the underlying physics, Dr. Pandey’s algorithms from the R50 award will also benefit the U01 grant. Dr. Pandey’s doctoral and postdoctoral training in developing advanced model-based (MB) algorithms for acoustic tomographic modalities and experience with XACT qualify him to achieve the proposed aims. MB reconstructions are computationally intensive and hence, graphics processing units-based acceleration will be implemented for achieving real-time/near real-time dose monitoring. The R50 award will provide protected time for Dr. Pandey to express his research creativity to grow into a seasoned research scientist and help...