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Background Despite its success in liquid tumors, patient response to immunotherapy in solid tumors remains scarce and unpredictable. It has been hypothesized that the presence of stroma in solid tumors presents a biophysical barrier that hinders drug penetration, immune cell infiltration and activation. Currently, there is a strong need for translational biomarkers that can accurately and reproducibly quantify the role of the stromal physical barrier and provide clinically translatable guidance to modulate it and restore response to immunotherapy. Such biomarkers may be used to guide the implementation of low-dose radiation (LD-XRT) or low-dose/high-dose protocols (RadScopal) in combination with immunotherapy to remodulate tumor stroma and restore or enhance response to immunotherapy in solid tumors.Methods In this work, we leverage ARTIDIS technology as a quantitative, clinically embedded, biomarker discovery platform to quantify biomechanical stromal barrier remodeling in solid tumors at the nanoscale resolution and guide the use of low-dose radiation to prime the tumor microenvironment and restore response to immunotherapy in a variety of solid tumors, in both preclinical models and clinical studies. We call this new class of biomarker, ‘nanomechanical signatures.’ Our preclinical work includes mouse models of lung; pancreatic and gastric cancer treated with a variety of low-dose radiation therapy protocols in combination with immune-checkpoint inhibitors and CAR-T cell therapy. Clinically, our study includes patients recruited under two different studies at MDACC: the Salvage Radiation Therapy in Treating Patients with Metastatic Cancer That Has Progressed After Systemic Immunotherapy ( NCT02710253, Phase II), and the Phase I/Ib Trial of TIraGolumab, AtEzolizumab, and RadScopal Radiation in Patients with Advanced Solid Malignancies (TIGER) study (NCT06760481, Phase I).Results Among our clinical results, initial exploratory evaluation of currently enrolled clinical cases reveals that ARTIDIS nanomechanical signature predicts the long term response to combination immunotherapy and RadScopal in advanced (stage IV) melanoma patients. Preclinical investigations into the combination of immune checkpoint inhibitors with low-dose radiation therapy demonstrated that nanomechanical signatures are predictive of immunotherapy response following radiation priming. Our preclinical studies include results from both immune-checkpoing inhibithors and CAR-T cell therapy in combination with LD-XRT protocols. Additionally, this approach detects activated T cells with exceptional sensitivity, specificity, and area-under-the-curve (AUC) performance, ranging between 90% and 99%.Conclusions Our preclinical and clinical results confirm that ARTIDIS-detected nanomechanical signatures can be implemented as a robust predictive biomarker to guide clinical applications of low-dose radiation therapy to enhance and restore response to immunotherapy in advanced solid tumors.Trial Registration Clinically, our study includes patients recruited under two different studies at MDACC: the Salvage Radiation Therapy in Treating Patients with Metastatic Cancer That Has Progressed After Systemic Immunotherapy ( NCT02710253, Phase II), and the Phase I/Ib Trial of TIraGolumab, AtEzolizumab, and RadScopal Radiation in Patients with Advanced Solid Malignancies (TIGER) study (NCT06760481, Phase I).Ethics Approval Clinically, we are currently recruiting patients under two different studies at MDACC: the Salvage Radiation Therapy in Treating Patients With Metastatic Cancer That Has Progressed After Systemic Immunotherapy ( NCT02710253), and the Phase I/Ib Trial of TIraGolumab, AtEzolizumab, and RadScopal Radiation in Patients With Advanced Solid Malignancies (TIGER) study (NCT06760481). All clinical studies were conducted in accordance with the principles outlined in the Declaration of Helsinki. This study protocol (MD Anderson Protocol Number: 2024-0309) was approved by the Institutional Review Board (IRB) of MD Anderson Cancer Center. All participants provided informed consent prior to their participation in the study. All animal experiments were conducted in strict accordance with institutional guidelines and regulations, and all protocols were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of The University of Texas MD Anderson Cancer Center under protocol number (00001018-RN04).