Decoding the pancreatic cancer microenvironment: The multifaceted regulation of microRNAs

Abstract

Pancreatic cancer (PC) is an extremely deadly type of cancer, and the 5-year survival rate remains less than 10%. The tumour microenvironment (TME) affects the occurrence, progression and treatment outcomes of PC. MicroRNAs (miRNAs) are essential to regulate PC TME. This review delves into the different roles of miRNAs in the PC TME, including exosome communication, angiogenesis, interactions with cancer-associated fibroblasts, the immunological and neuronal microenvironments and metabolic reprogramming. However, research on the complex regulatory networks and synergistic effects of miRNAs in the TME is still insufficient, and their clinical translation and application face challenges. This review summarised the activities of miRNAs in the PC TME, guiding future research and therapeutic strategies involving miRNAs in PC. Future studies should integrate advanced technologies to decode the spatiotemporal dynamics of miRNA regulation within the TME and develop optimised nanodelivery systems for stable and targeted miRNA delivery, advancing clinical applications in PC treatment.

Keywords: PC; exosome; immune microenvironment; miRNA; tumour microenvironment.

FIGURE 1

Composition of the TME. The TME comprises diverse immune cell populations including macrophages, dendritic cells (DCs), myeloid‐derived suppressor cells (MDSCs), T lymphocytes, natural killer (NK) cells, neutrophils and B lymphocytes, stromal elements including CAFs, vascular endothelial cells and structural components including lymphatic vessels, neurons, exosomes, the extracellular matrix and blood vessels, which collectively contribute to immunosuppressive and tumour‐promoting niche characteristics.

FIGURE 2

Exosomal miRNA regulation of the TME in PC. (A) Tumour‐derived exosomal miRNAs modulate the PC cells malignant behaviours and drug resistance of PC cells. (B) Exosomal miRNAs carried by PC cells promote the activation of PSCs. Communication between PSC‐derived exosomal miRNAs and tumour cells plays a key role in PC progression. (C) PC cell‐derived exosomal miRNAs contributing to fat atrophy, diabetes and bone loss caused by PC. Red text indicates miRNAs that promote PC progression, whereas blue text denotes miRNAs that suppress tumour development.

FIGURE 3

miRNA modulation of angiogenesis in PC. Tripartite regulatory mechanisms of miRNAs governing angiogenesis include anti‐angiogenic inhibition (A), proangiogenic activation (B) and hypoxia‐induced vascular remodelling (C) in the TME of PC. Red text indicates miRNAs that promote PC progression, whereas blue text denotes miRNAs that suppress tumour development.

FIGURE 4

Interplay between miRNAs in PC cells and CAFs. (A) Exosomal miRNAs from CAFs modulate oncogenic pathways in PC cells. (B) Tumour‐secreted exosomal miRNAs reprogrammed NFs into CAFs. (C) Regulatory feedback loops involving cytokine and signalling pathways among CAFs and PC cells. Red text indicates that miRNAs promoting the advancement of PC, whereas blue text denotes miRNAs that suppress tumour development.

FIGURE 5

Dual functions of miRNAs in the management of immune cells in PC. (A) Key miRNAs involved in inducing TAMs to repolarise from the pro‐tumour M2‐type to the anti‐tumour M1‐type, thereby enhancing anti‐tumour immunity. (B) Exosomal miRNAs derived from M2 macrophages influence PC progression. (C) Key miRNAs involved in inducing TAMs to repolarise from the anti‐tumour M1‐type to the pro‐tumour M2‐type, thereby promoting PC development. (D) miRNA‐mediated modulation of DC activation and antigen presentation. (E) miRNAs governing MDSC activity. (F) miRNAs that potentiate or attenuate T‐cell anti‐tumour activity. (G) miRNAs that influence immune cell proportions. (H) miRNAs governing NK cell function. Red text indicates that miRNAs weaken anti‐tumour immunity, whereas blue text denotes that miRNAs enhance anti‐tumour immunity.

FIGURE 6

Regulation of glycolysis and glutamine metabolism by miRNAs. miRNAs exert coordinated regulation over critical metabolic enzymes, including HK2, PFK, PKM2 and LDHA, in glycolysis, as well as ASCT2 and GOT1 in glutamine metabolism, while interfacing with central signalling pathways. The text in the blue box indicates miRNAs that suppress tumour development.