Nano-Drug Delivery Systems Targeting CAFs: A Promising Treatment for Pancreatic Cancer

Abstract

Currently, pancreatic cancer (PC) is one of the most lethal malignant tumors. PC is typically diagnosed at a late stage, exhibits a poor response to conventional treatment, and has a bleak prognosis. Unfortunately, PC's survival rate has not significantly improved since the 1960s. Cancer-associated fibroblasts (CAFs) are a key component of the pancreatic tumor microenvironment (TME). They play a vital role in maintaining the extracellular matrix and facilitating the intricate communication between cancer cells and infiltrated immune cells. Exploring therapeutic approaches targeting CAFs may reverse the current landscape of PC therapy. In recent years, nano-drug delivery systems have evolved rapidly and have been able to accurately target and precisely release drugs with little or no toxicity to the whole body. In this review, we will comprehensively discuss the origin, heterogeneity, potential targets, and recent advances in the nano-drug delivery system of CAFs in PC. We will also propose a novel integrated treatment regimen that utilizes a nano-drug delivery system to target CAFs in PC, combined with radiotherapy and immunotherapy. Additionally, we will address the challenges that this regimen currently faces.

Keywords: cancer-associated fibroblasts; nano-drug delivery system; nanoparticle; pancreatic cancer; tumor microenvironment.

Figure 1

Effects of CAFs on pancreatic cancer cells can be categorized into tumor-promoting and tumor-suppressing effects. Tumor suppressive effects mainly include increasing chemosensitivity, reducing malignancy, inhibiting self-renewal of cancer cells, and promoting anti-tumor immunity mainly by T cells. Tumor-promoting effects mainly involve the production of a series of substances by CAFs, such as FAP, EVs, exocrine bodies, TGF-β, and others. These substances can promote the functions of ECM generation, stromal expansion and suppression of tumor immunity. Created with BioRender.com.

Figure 2

Mechanisms of therapy resistance in pancreatic cancer orchestrated by CAFs. The diagram situated in the upper left quadrant elucidates the precise molecular pathways through which CAFs instigate resistance to chemotherapy. Similarly, the diagram positioned in the upper right quadrant delineates the specific molecular mechanisms underpinning CAF-induced radiotherapeutic resistance. The diagram located in the lower section of the illustration delineates the intricate molecular interactions between CAFs, diverse immune cells, immune-related molecules, and the immunological microenvironment, elucidating the underlying causes of immunosuppression. Created with BioRender.com.

Figure 3

Drug delivery via nano-drug delivery system acting on pancreatic cancer-associated CAFs. A variety of nanoparticles (in combination with each other or in combination with chemotherapeutic agents) are assembled into nano-drug delivery systems that are capable of aggregating towards the pancreas upon entry into the body. They are able to penetrate the TME with relative ease and target CAFs and the organelles within them. This approach may have the effect of interfering with the pro-tumorigenic function of CAFs to treat pancreatic cancer. Created with BioRender.com.