Integration of multi-modal imaging techniques and various cancer treatments based on their respective characteristics would be beneficial for enhancing anticancer efficacy. Exploiting an "all-in-one" nanoparticle with high biocompatibility has attracted widespread attention. Herein, two clinically proven modalities, human serum albumin (HSA) and indocyanine green (ICG), were selected to create HSA-stable barium sulfonate nanoparticles (HSA@ICG-Ba) through the reaction of a sulfonic acid group with barium ions. Our nano-probe showed excellent optical properties and X-ray absorption capacity, which can be applied in tumor theranostics. Utilizing the rich tumor accumulation of HSA@ICG-Ba, this nanoparticle can obtain multifaceted tumor information through fluorescence (FL), computerized tomography (CT), photoacoustic (PA) imaging, and single photon emission computed tomography (SPECT) imaging. Additionally, radiation sensitization therapy and photothermal therapy based on HSA@ICG-Ba were evaluated using both in vitro and in vivo models. The efficacy of tumor radiotherapy can be further improved by mild hyperthermia owing to the relieved tumor hypoxia. Finally, the favorable safety profile of HSA@ICG-Ba is confirmed by blood index analysis and tissue section observation. Therefore, this study explored an "all-in-one" barium sulfonate nanoparticle with high biocompatibility for FL/CT/PA/SPECT imaging-guided synergetic photothermal-radiotherapy of tumors, providing a new approach and potential pathway for tumor theranostics.