# Matrix Metalloproteinases in Hepatocellular Carcinoma: Mechanistic Roles and Emerging Inhibitory Strategies for Therapeutic Intervention

## TL;DR

This review explores how matrix metalloproteinases (MMPs) contribute to liver cancer progression and highlights new strategies for targeting them to improve treatment outcomes.

## Contribution

The paper presents emerging strategies for precise and safer targeting of MMPs in liver cancer therapy.

## Key findings

- MMPs facilitate tumor expansion, tissue invasion, and metastasis by altering the extracellular matrix.
- Aberrant MMP activity is linked to aggressive cancer features and poor patient survival.
- Recent advances in molecular design and nanotechnology enable more selective MMP inhibition with potential therapeutic benefits.

## Abstract

Liver cancer, particularly hepatocellular carcinoma, is a highly aggressive disease with limited treatment options and poor outcomes for many patients. A major reason for cancer spread and treatment resistance is the ability of tumor cells to reshape their surrounding tissue environment. Matrix metalloproteinases (MMPs) are enzymes that play a central role in this process by remodeling tissue structure, promoting tumor invasion, altering blood vessel formation, and influencing immune responses. This review summarizes current knowledge on how these enzymes contribute to liver cancer development and progression and discusses why earlier drugs targeting them were unsuccessful. Importantly, it highlights recent advances that allow more precise and safer targeting of specific enzymes or pathways. These emerging strategies may help improve existing therapies, reduce tumor recurrence, and guide future research toward more effective and personalized treatment approaches for liver cancer.

Liver cancer, also known as hepatocellular carcinoma (HCC), remains a major global health concern, with high mortality driven by late-stage diagnosis, limited treatment efficacy, and frequent therapeutic resistance. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, are central to the biological processes that drive liver tumor initiation and progression. By degrading and reorganizing extracellular matrix components, MMPs facilitate tumor expansion, tissue invasion, and metastatic dissemination. In addition, these enzymes regulate the availability of growth factors, cytokines, and chemokines, thereby influencing angiogenesis, inflammation, immune cell recruitment, and the development of an immunosuppressive tumor microenvironment. Aberrant expression or activity of multiple MMP family members is consistently associated with aggressive clinicopathologic features, including vascular invasion, increased metastatic potential, and reduced patient survival, highlighting their promise as prognostic markers and actionable therapeutic targets. Past attempts to modulate MMP activity were hindered by broad inhibition profiles and dose-limiting toxicities, underscoring the need for improved specificity and delivery strategies. Recent advances in molecular design, biologics engineering, and nanotechnology have revitalized interest in MMP targeting by enabling more selective, context-dependent modulation of proteolytic activity. Preclinical studies demonstrate that carefully tuned MMP inhibition can limit tumor invasion, enhance anti-angiogenic responses, and potentially improve the efficacy of existing systemic therapies, including immuno-oncology agents. This review synthesizes current knowledge on the multifaceted roles of MMPs in HCC pathobiology and evaluates emerging therapeutic strategies that may finally unlock the clinical potential of targeting these proteases.