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The PD‐1 immune checkpoint‐based therapy has emerged as a promising therapy strategy for treating the malignant brain tumor glioblastoma (GBM). However, patient response varies in clinical trials, mainly due to the tumor heterogeneity and immunological resistance in the tumor microenvironment. To further understand how mechanistically the niche interplay and competition drive anti‐PD‐1 resistance, an in silico model is established to quantitatively describe the biological rationale of critical GBM‐immune interactions, such as tumor growth and apoptosis, T cell activation and cytotoxicity, and tumor‐associated macrophage (TAM) mediated immunosuppression. Such an in silico experimentation and predictive model, based on the in vitro microfluidic chip‐measured end‐point data and patient‐specific immunological characteristics, allows for a comprehensive and dynamic analysis of multiple TAM‐associated immunosuppression mechanisms against the anti‐PD‐1 immunotherapy. The computational model demonstrates that the TAM‐associated immunosuppression varies in severity across different GBM subtypes, which results in distinct tumor responses. The prediction results indicate that a combination therapy by co‐targeting of PD‐1 checkpoint and TAM‐associated CSF‐1R signaling can enhance the immune responses of GBM patients, especially those patients with mesenchymal GBM who are irresponsive to the single anti‐PD‐1 therapy. The development of a patient‐specific in silico–in vitro GBM model will help navigate and personalize immunotherapies for GBM patients.

Cancer stem‐like cells (CSCs) have been shown to initiate tumorigenesis and cancer metastasis in many cancer types. Although identification of CSCs through specific marker expression helps define the CSC compartment, it does not directly provide information on how or why this cancer cell subpopulation is more metastatic or tumorigenic. In this study, the functional and biophysical characteristics of aggressive and lethal inflammatory breast cancer (IBC) CSCs at the single‐cell level are comprehensively profiled using multiple microengineered tools. Distinct functional (cell migration, growth, adhesion, invasion and self‐renewal) and biophysical (cell deformability, adhesion strength and contractility) properties of ALDH+ SUM149 IBC CSCs are found as compared to their ALDH− non‐CSC counterpart, providing biophysical insights into why CSCs has an enhanced propensity to metastasize. It is further shown that the cellular biophysical phenotype can predict and determine IBC cells' tumorigenic ability. SUM149 and SUM159 IBC cells selected and modulated through biophysical attributes—adhesion and stiffness—show characteristics of CSCs in vitro and enhance tumorigenicity in in vivo murine models of primary tumor growth. Overall, the multiparametric cellular biophysical phenotyping and modulation of IBC CSCs yields a new understanding of IBC's metastatic properties and how they might develop and be targeted for therapeutic interventions.