Manipulation of immune‒vascular crosstalk: new strategies towards cancer treatment

Abstract

Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors, endogenous immune surveillance and immune cell function. Vascular normalization as a novel therapeutic strategy tends to prune some of the immature blood vessels and fortify the structure and function of the remaining vessels, thus improving immune stimulation and the efficacy of immunotherapy. Interestingly, the presence of “immune‒vascular crosstalk” enables the formation of a positive feedback loop between vascular normalization and immune reprogramming, providing the possibility to develop new cancer therapeutic strategies. The applications of nanomedicine in vascular-targeting therapy in cancer have gained increasing attention due to its specific physical and chemical properties. Here, we reviewed the recent advances of effective routes, especially nanomedicine, for normalizing tumor vasculature. We also summarized the development of enhancing nanoparticle-based anticancer drug delivery via the employment of transcytosis and mimicking immune cell extravasation. This review explores the potential to optimize nanomedicine-based therapeutic strategies as an alternative option for cancer treatment.

Microbial proteases: ubiquitous enzymes with innumerable uses

“…Last few decades have enhanced our knowledge to explore the applications of these enzymes in industries beyond the food technology, like textiles, leather, detergent, agriculture, and pharmaceutical industry. The ‘era of OMICS’ has further provided future directions of utilizing proteolytic potential of these enzymes in nanotechnology and site-specific or targeted drug delivery systems (Zhao et al 2020 ), as well as for imaging technology in cancer diagnostics (Abousaway et al 2021 ). Novel engineered proteases activated by small molecules hold the future of specifically controlling the activity of human proteases, and significantly changing the course of cell cycle and probably even cell death (Gerry and Schreiber 2020 ).…”

Combined Blockade of GARP:TGF-β1 and PD-1 Increases Infiltration of T Cells and Density of Pericyte-Covered GARP+ Blood Vessels in Mouse MC38 Tumors

“…Intratumoral blood vessels are often described as structurally abnormal, displaying loose cellular junctions, high number of fenestrations and discontinuous basement membrane, which can impair lymphocyte extravasation ( 17 ). To measure the functionality and stability of blood vessels, we used anti-PDGFRβ antibodies to identify blood vessels covered by pericytes ( i.e.…”

“…No increase in the density of PDGFRβ-negative blood vessels was observed in either MC38 or CT26 tumors, whatever the treatment ( Figure 4B ). Thus, increased blood vessel density in MC38 tumors after GARP:TGF-β1/PD-1 blockade can be attributed to an increased density of those vessels that are stabilized by pericytes, a parameter often taken as an indicator of blood vessel normalization in tumors ( 17 ).…”

“…This would explain the densification of pericyte-covered blood vessels observed in MC38 tumors upon combined GARP:TGF-β1/PD-1 blockade. Increased density of pericyte-covered blood vessels is an indicator of tumor vasculature normalization, which could improve tumor perfusion ( 17 , 28 ). Other approaches targeting the tumor vasculature to overcome resistance to PD-1/PD-L1 blockade were tested previously, e.g.…”

Editorial of Special Issue on Tumor Microenvironment and Drug Delivery

“…Li et al. 5 summarized the function of tumor vasculature and the immune-vascular crosstalk in tumors. Then they proposed strategies towards tumor vascular normalization.…”