Modulating cancer mechanopathology to restore vascular function and enhance immunotherapy

Abstract

Solid tumor pathology, characterized by abnormalities in the tumor microenvironment (TME), challenges therapeutic effectiveness. Mechanical factors, including increased tumor stiffness and accumulation of intratumoral forces, can determine the success of cancer treatments, defining the tumor's "mechanopathology" profile. These abnormalities cause extensive vascular compression, leading to hypoperfusion and hypoxia. Hypoperfusion hinders drug delivery, while hypoxia creates an unfavorable TME, promoting tumor progression through immunosuppression, heightened metastatic potential, drug resistance, and chaotic angiogenesis. Strategies targeting TME mechanopathology, such as vascular and stroma normalization, hold promise in enhancing cancer therapies with some already advancing to the clinic. Normalization can be achieved using anti-angiogenic agents, mechanotherapeutics, immune checkpoint inhibitors, engineered bacterial therapeutics, metronomic nanomedicine, and ultrasound sonopermeation. Here, we review the methods developed to rectify tumor mechanopathology, which have even led to cures in preclinical models, and discuss their bench-to-bedside translation, including the derivation of biomarkers from tumor mechanopathology for personalized therapy.

Keywords: anti-angiogenic therapy; biomarkers; engineered bacteria; precision oncology; tumor normalization.

Graphical abstract

Figure 1

Tumor mechanopathology shapes the tumor vascular system and poses major barriers to treatment efficacy (A) The abnormal proliferation of cancer cells within the constrained environment of the normal host tissue, along with interactions among stromal cells and the fibrotic ECM, contribute to the mechanopathology of the tumor. The hallmarks of tumor mechanopathology consist of (1) the accumulation of mechanical forces and the ECM stiffening, (2) the chaotic formation of new blood vessels via the process of angiogenesis, and (3) the increased interstitial fluid pressure (IFP) due to vessel compression and abnormal leakiness of the newly formed tumor blood vessels. (B) Tumor stiffening and accumulation of intratumoral mechanical forces that are exerted on tumor blood vessels cause vessel compression and reduce tumor perfusion. The chaotic nature of angiogenesis contributes to a poorly perfused tumor microenvironment, affecting the overall blood circulation and influencing the responsiveness of the tumor to therapeutic interventions. Hyper-permeability of some tumor blood vessels results in fluid leakage from the vascular to the extravascular space, which increases fluid pressure in the tumors (IFP) and also contributes to hypoperfusion. Impaired blood supply and hypoxia not only reduce drastically drug delivery but also help cancer cells evade the immune system and increase their invasive and metastatic potential. Particularly, hypoperfusion hinders immune cells infiltration into the tumor, while hypoxia renders the TME immunosuppressive and promotes pro-tumor immune responses. Created with BioRender.com.

Figure 2

Tumor mechanopathology compromises anti-tumor immune response The immunity cycle against cancer is a self-perpetuating loop consisting of seven key stages, beginning with antigen release from cancer cells and culminating in their destruction. The figure details each stage, identifying the principal cell types and anatomical regions involved in each step. Abnormalities in the TME can negatively affect the trafficking and infiltration of the immune cells into the tumor, induce immunosuppression and tumor-associated macrophage polarization, and compromise antigen presentation, creating a feedback loop that hinders anti-tumor immune responses. Key abbreviations include APCs for antigen-presenting cells, CTLs for cytotoxic T cells, TAMs for tumor-associated macrophages, MHC for major histocompatibility complex, and ICD for immunogenic cell death. Created with BioRender.com.

Figure 3

Therapeutic approaches targeting tumor mechanopathology (A) Schematic of proposed mechanism of action of normalization strategies to improve cancer therapy. The normalization of the tumor microenvironment involves the restoration of vascular functionality and the decompression of tumor blood vessels through the targeting of ECM components. This process leads to enhanced tumor perfusion and oxygenation, fostering the activation of effector immune cells and reducing the presence of immune system regulator cells. Furthermore, it causes a shift in TAM polarization from the immunosuppressive M2-like phenotype to the M1-like phenotype. As a result, there is an increase in drug delivery efficiency and the potency of cancer cell elimination. (B) Grade of the effect of various proposed therapeutic strategies in vascular and stroma normalization. Vascular normalization restores in a great manner the abnormalities in the tumor vasculature to a more functional phenotype using anti-angiogenic agents targeting VEGF, PDGF-B, HIF, and Ang1/2. Mechanotherapeutics normalize tumor stroma and vasculature by targeting ECM components, through reprogramming of CAFs and/or by targeting VEGF and interferon-γ. Metronomic therapy induces moderate effects in vessels and stroma components via the frequent administration of chemotherapeutic drugs at lower doses than MTD. It can induce vascular normalization by increasing the levels of the endogenous angiogenesis inhibitor thrombospondin-1. Administration of ICIs can improve pericyte coverage by overexpressing interferon-γ. Engineered bacteria are alternative agents than mechanotherapeutics, which induce stroma normalization via ECM degradation and vascular normalization by targeting VEGF or matrix metalloproteinases.^, Created with BioRender.com.

Figure 4

Biomarkers predictive of response can be used to guide therapy and benefit non-responder patients Ultrasound shear wave elastography, atomic force microscopy, and magnetic resonance elastography-derived measures of tumor stiffness and ultrasound contrast-enhanced ultrasound and PET scan-derived measures of perfusion and oxygenation can predict response to cancer therapy and guide the use of normalization agents to potentiate therapy in non-responders.