# Multifaceted Attack Networks of Artemisinin in Reversing Chemoresistance in Colorectal Cancer

## TL;DR

This review explores how artemisinin and its derivatives can reverse chemotherapy resistance in colorectal cancer through multiple mechanisms, including immune modulation and cell death strategies.

## Contribution

The paper introduces a multidimensional attack network framework to explain the synergistic effects of artemisinin-derived compounds in overcoming CRC chemoresistance.

## Key findings

- ADs suppress cancer stem cell resistance and reshape the tumor immune microenvironment.
- ADs induce apoptosis and ferroptosis as dual-track cell death mechanisms.
- ADs modulate pro-survival and immune pathways, including immunogenic cell death and macrophage subsets.

## Abstract

Chemotherapy resistance in colorectal cancer (CRC) represents a critical clinical challenge leading to treatment failure and poor patient prognosis. Artemisinin is a natural product isolated from Artemisia annua, and its clinically relevant derivatives include dihydroartemisinin (DHA) and artesunate. Beyond their established antimalarial efficacy, both artemisinin and its derivatives—collectively referred to as artemisinin-derived compounds (ADs)—have been increasingly recognized for their unique potential to reverse multidrug resistance in cancer. Unlike previous reviews focusing on isolated mechanisms, this review systematically constructs a multidimensional, synergistic attack network centered on ADs to elucidate their integrated actions against chemotherapy-resistant CRC. Mechanistically, ADs suppress cancer stem cell (CSC)-associated resistance phenotypes while concurrently reshaping the tumor immune microenvironment, highlighting a functional coupling between stemness inhibition and immune remodeling. In parallel, this review presents apoptosis reactivation and ferroptosis induction as complementary, dual-track cell death strategies that collectively circumvent apoptosis resistance. Moreover, ADs exert “one-strike–multiple-effects” through coordinated regulation of pro-survival signaling networks and immune-related pathways, including the induction of immunogenic cell death (ICD) and the modulation of immunosuppressive macrophage subsets. Beyond mechanistic insights, this review integrates emerging translational considerations, including clinical pharmacokinetics, safety and tolerability, formulation and delivery strategies, and rational combination therapy paradigms in CRC. Collectively, these findings position ADs as multi-dimensional modulators rather than a single-agent cytotoxic, providing a coherent mechanistic and translational rationale for their further development in chemotherapy-resistant CRC.