In Chapter 1, we developed cell-free DNA (cfDNA) biomarkers. Standard-of-care for patients with localized muscle-invasive bladder cancer is neoadjuvant chemotherapy followed by radical cystectomy. Bladder-sparing treatments are limited by our current inability to sensitively detect minimal residual disease (MRD). To address this, we focused on the biofluid most proximal to disease, urine, and analyzed cfDNA from 84 localized bladder cancer patients. We applied two orthogonal molecular approaches: low-pass whole genome sequencing (LP-WGS) and genome-wide 5-hydroxymethylcytosines (5hmC) profiling in order to achieve sensitive MRD detection. Using LP-WGS, we computed copy-number derived tumor fraction (TFx) and found that patients who had not achieved complete response (no pCR), as determined by gold-standard surgical pathology, had significantly higher TFx levels than those with complete response. A classifier for predicting residual disease based on TFx achieved a receiver operating curve area under the curve (ROC AUC) of 0.78 but did not predict patient overall survival. We then developed a 5hmC-based model based on a 25-gene marker panel for predicting MRD which achieved an ROC AUC of 0.91. The panel contained a number of independently prognostic genes implicated in carcinogenesis. Patients predicted to have MRD based on the 5hmC model had worse progression-free survival and overall survival. In summary, we provided proof-of-principle that urine cfDNA omics approaches can noninvasively detect MRD and reveal potentially new onco-relevant targets. In the second chapter, we used a murine preclinical metastasis model to identify mechanisms of radioresistance. Previous work from Piffko et al. had identified amphiregulin (AREG), an EGFR ligand, as a key factor in driving metastatic growth in non-irradiated lesions in patients receiving stereotactic body radiotherapy (SBRT). To identify immune mechanisms of AREG-mediated metastasis, we performed single-cell RNA sequencing (scRNA-seq) of CD45+ cells in lung tissues following radiotherapy of flank tumors. Our analysis revealed that AREG triggered distinct transcriptional changes in mononuclear phagocytes(MNPs), especially inflammatory monocytes. These changes included upregulation of immunosuppressive and downregulation of inflammatory and antigen-presenting pathways. Moreover, there was a marked increase in EGFR signaling in inflammatory monocytes following irradiation, providing a link between AREG-mediated EGFR signaling activation and the immunosuppressive phenotype. A monocyte trajectory analysis unveiled that AREG led to divergent differentiation trajectories in monocytes, with some populations arrested at an immature, immune-suppressive state while others followed a tumor-tolerogenic trajectory. Building on the findings from Piffko et al., we suggest a model where radiation-induced soluble growth factors modulate the host immune response, potentially offering therapeutic targets to significantly improve patient outcomes in the future.