A mechanical reprogramming: synergistic tumor microenvironment normalization improves nano-immunotherapy delivery in prostate cancer via multiphysics modeling.

There is a poor response of prostate cancer to immunotherapies because of dysfunctions in the tumor microenvironment (TME) characteristics, like abnormal vasculature structure, stiffened stroma, increased interstitial fluid pressure (IFP), and regions of hypoxia. However, the existing computational modelings are unable to tackle this issue, as they are based on two-dimensional (2D) geometry that ignores TME properties (like TME biphasic composition) and interaction between cancer and immune cells. To address this knowledge gap, this paper offers a patient-specific multiphysics model for prostate cancer. The proposed model is based on three-dimensional (3D) geometry obtained from magnetic resonance imaging (MRI) and combines three complementary approaches to normalizing the tumor microenvironment: vascular normalization via anti-angiogenic therapy, stromal normalization via extracellular matrix softening, and immune checkpoint blockade. One important new aspect of this work is that new nanoparticle delivery models have been developed for 20-100 nm nanoparticles (NP) delivering immunotherapy agents. These equations explicitly incorporate interactions between the components of the TME and directly account for mechanical stress induced by tumor growth, enabling mathematical modeling of physical TME changes and their subsequent impact on the dynamics of immune cells (such as cytotoxic T cells (CD8 + T cells), regulatory T cells (Treg), and pro-inflammatory macrophages (M1-like)/anti-inflammatory macrophages (M2-like) and cancer cells. This capability is absent in previous models. The other important novelty is that for the first time in a prostate cancer model, factors for vascular and stromal normalization and immunotherapy have been incorporated in a 3D geometry. The parameters of this model have been optimized based on literature and preclinical trial data related to immunology and tumors. The sensitivity analysis has confirmed that all therapeutic factors, optimized vascular function (functional vessel density increases from 43 to 112 cm/cm), reduced stromal solid stress (decrease in shear modulus from 10.4 to 6.1 kPa), as well as a 70% reduction in IFP (from 1471 to 441 Pa), in combination contribute to a 30% increase in accumulation of nanoparticles in the tumor, 60% increase in the ratio of CD8 + /Tregs, a 45% decrease in the ratio of M1/M2 macrophages, a 15% reduction in the tumor hypoxia gradient, and a 40% decrease in the size of the tumor within 50 days. This model can thus provide a clinically applicable tool for predicting the efficacy of nano-immunotherapy in prostate cancer. Experimental confirmation is required to better evaluate NP toxicity.