# Immune and Tumor Microenvironment Mechanisms of Hedyotis diffusa Willd: A Scoping Review and Network Pharmacology Analysis

## TL;DR

This study explores how the herbal medicine Hedyotis diffusa Willd affects cancer growth and the immune system, using both lab research and computational analysis.

## Contribution

The study provides a comprehensive synthesis of HDW's effects on the tumor microenvironment and immune responses using a scoping review and network pharmacology.

## Key findings

- HDW suppresses cancer cell growth and reduces harmful inflammation through multiple biological pathways.
- HDW enhances anticancer immune activity and inhibits tumor angiogenesis and EMT in preclinical models.
- Network analysis identified key signaling pathways like PI3K-Akt and STAT3 as central to HDW's mechanisms.

## Abstract

Cancer growth is strongly influenced by its surrounding environment, which includes immune cells, blood vessels, and supporting tissues. Many traditional herbal medicines are used alongside cancer care, but their effects on this tumor environment are not always clearly understood. Hedyotis diffusa Willd (HDW) is a commonly used herb in East Asian medicine, yet its actions on immune responses and the tumor environment have not been comprehensively summarized. In this study, we reviewed existing laboratory research and combined it with computational network analysis to understand how this herb may work. We found that HDW can suppress cancer cell growth, reduce harmful inflammation, and support anticancer immune activity through multiple biological pathways. These findings provide an integrated picture of how this herbal medicine may influence cancer-related immune and microenvironmental processes, offering a useful reference for future experimental and translational research.

Background: The tumor microenvironment (TME) is a dynamic ecosystem that critically shapes tumor progression, immune escape, and therapeutic responses. Hedyotis diffusa Willd (HDW) has long been used in East Asian medicine for conditions associated with inflammation and malignancy, yet its immunological and microenvironmental mechanisms have not been systematically synthesized. Methods: A scoping review of preclinical studies (2016–2025) was conducted following the Arksey-O’Malley framework and PRISMA-ScR guidance to systematically map experimental evidence on the antitumor, immune-related, and TME-associated effects of HDW. To complement and interpret these heterogeneous experimental findings at a systems level, a network pharmacology analysis was performed to identify bioactive compounds, predict their putative protein targets, and assess their convergence on immune- and microenvironment-related signaling networks through protein-protein interaction and pathway enrichment analyses. Results: Fifty-nine studies met eligibility criteria, encompassing in vitro and in vivo models across diverse cancer types. Experimental evidence from preclinical models showed that HDW extracts and bioactive fractions consistently suppressed proliferation, induced apoptosis and ferroptosis, inhibited epithelial-mesenchymal transition (EMT) and angiogenesis, and enhanced cytotoxic lymphocyte activity, while attenuating tumor-associated inflammation. In parallel, in silico network analysis identified 94 intersecting immune- and TME-related targets and revealed a densely connected interaction network centered on PI3K-Akt, STAT3, EGFR, and SRC. Enrichment analyses highlighted receptor tyrosine kinase signaling, inflammatory pathways, metabolic regulation, and focal adhesion as dominant functional themes. Conclusions: HDW acts as a multi-target botanical agent that integrates direct cytotoxicity with immune activation and TME remodeling. Network-in-formed interpretation indicates that the modulation of PI3K-Akt-STAT3 signaling is a common mechanistic axis linking experimental observations.