Abstract 4637: Nanomechanical signatures: novel class of clinically translatable biomarkers to predict response to immunotherapy in advanced solid tumors

Abstract Background: Advancements in immunotherapy have opened new avenues for the treatment of solid tumors. However response remains poor, especially in case of advanced tumors where resistance to immunotherapy after initial response remains a significant challenge. In recent years it has become evident that mechanical properties of tumor and immune cells as well as of the tumor microenvironment (TME) pose an upstream challenge to efficacy of a variety of therapeutics, including immunotherapy. Approaches such as pretreatment with low-dose radiation therapy (LD-RT) to remodulate the physical tumor microenvironment in combination have shown promise in clinics, reporting as effective as fully extinguishing detectable tumors in patients with previously stage IV tumors in lung and liver. Accurate prediction of benefit by such strategies is of outmost importance. In this work, we report on a novel class of predictive, tumor-agnostic biomarkers for combination immunotherapies: nanomechanical signatures. Methods: To characterize the nanomechanical signature, the clinically-embedded, tissue-preserving AFM-based Automated and Reliable Tissue Diagnostics (ARTIDIS) platform is used. ARTIDIS multimodal analysis includes integration with available histopathological and clinical data. Two preclinical models are used: PD1-resistant lung adenocarcinoma on 129Sv/Ev mice, and gastric cancer on NSG mice, treated with anti-CTLA and anti-PD1 in combination with LD-XRT and anti-mesothelin CAR-T cell therapy in combination with LD-XRT, respectively. Case reports from patients with advanced metastatic solid cancers resistant to immunotherapy enrolled under the on-going ARTIDIS Umbrella protocol at MDACC are also included. Results: Our preclinical studies identify the nanomechanical signature of response to low-dose radiation and immunotherapy with high sensitivity, specificity and AUC (90%-99%). Furthermore, we can identify the unique nanomechanical signature of T cell infiltration. Our clinical studies confirm that a unique nanomechanical signature reflects TME remodulation in different therapeutic regiments among similar clinical and histopathological cases. Conclusions. In this work we demonstrated across different therapeutic strategies, preclinical tumor models and clinical cases that the nanomechanical signature can quantitatively describe the TME remodulation upon LD-XRT that mediates restored response to immunotherapy. This work supports the use of nanomechanical signature as predictive biomarker of response to immunotherapy to be used to support clinical decision making. Citation Format: Sara Nizzero, Nahum Puebla-Osorio, Gitika Srivastava, Reinier Oropesa Nuñez, Kathleen Graham, Papa Diogop Ndiaye, Joylise Mitchell, Ailing Huang, Thomas Riad, Carolina Ortiz-Velez, Sienna Welsh, Philipp Oertle, Tobias Appenzeller, Vittorio Cristini, Marko Loparic, Marija Plodinec, James W. Welsh. Nanomechanical signatures: novel class of clinically translatable biomarkers to predict response to immunotherapy in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4637.