A new study reveals that malignant transformation of intestinal stem cells (ISCs) and their supportive microenvironment (niche) drives colorectal cancer initiation, therapy resistance, and relapse. Targeting the ISC–cancer stem cell (CSC) ecosystem offers a breakthrough strategy to overcome treatment failure and develop next‑generation precision care for colorectal cancer patients.
Colorectal cancer remains one of the most common and deadly cancers worldwide, with high rates of recurrence, metastasis, and drug resistance despite advances in surgery, chemotherapy, targeted therapy, and immunotherapy. A new review published in Advanced Cancer Research explains why standard treatments often fall short—and points to a revolutionary solution: targeting intestinal stem cells and their malignant niche.
Led by researchers from Zhengzhou University, the work systematically maps how normal intestinal stem cells (ISCs) turn malignant, form cancer stem cells (CSCs), and reshape their surrounding microenvironment to survive treatment, evade immunity, and drive tumor regrowth.
“Colorectal cancer is not just a mass of dividing cells; it is a hierarchical ecosystem governed by plastic, treatment‑resistant cancer stem cells,” said corresponding author Prof. Pingping Zhu from the School of Life Sciences, Zhengzhou University, and State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer. “Conventional therapies kill fast‑growing cancer cells but often leave quiescent, highly plastic CSCs untouched. These cells are the real root of recurrence and metastasis.”
The study identifies three core drivers of treatment failure:
Oncogenic mutations (APC, KRAS, TP53) hijack stem cell pathways including Wnt, Notch, and Hippo–YAP to sustain uncontrolled stemness.
CSC plasticity allows differentiated cancer cells to revert back to stem‑like states, refueling tumors after therapy.
Immune evasion by CSCs weakens antigen presentation, suppresses anti‑tumor immunity, and makes “cold” tumors unresponsive to immunotherapy.
By analyzing recent preclinical and clinical advances, the team outlines a new precision medicine framework focused on the ISC–CSC–niche ecosystem, with six promising therapeutic strategies:
Inhibiting core stemness pathways (Wnt, Notch) to block self‑renewal
Using small molecules, antibodies, and antibody–drug conjugates (ADCs) to target CSC surface markers such as Lgr5, CD44, and CD133
Applying synthetic lethality to selectively kill APC‑mutant or KRAS‑mutant CSCs
Using sequential “prime‑then‑kill” therapy to induce differentiation and eliminate hidden stem‑like cells
Developing CSC‑targeted immunotherapies including vaccines, bispecific antibodies, and CAR‑T cells
Remodeling the tumor microenvironment and gut microbiota to turn “cold” tumors “hot”
The review also highlights cutting‑edge tools accelerating translation: patient‑derived organoids, spatial multi‑omics, single‑cell sequencing, and gut‑on‑chip models. These technologies allow researchers to mimic patient tumors in the lab, test drugs individually, and understand CSC behavior in realistic 3D environments.
“For the first time, we can systematically target the cellular roots of colorectal cancer rather than just shrink tumors,” Prof. Zhu added. “This paradigm shift will help us achieve durable remission and truly personalized care.”
The authors note challenges remain, including on‑target toxicity to normal stem cells, tumor heterogeneity, and adaptive resistance. However, ongoing clinical trials—such as Lgr5‑targeted CAR‑T and KRASG12C combination therapies—already show encouraging signals.
This work was supported by the National Natural Science Foundation of China, Henan Province Outstanding Youth Science Foundation, and the State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer.
This paper ”Malignancies of ISCs and their niche emerge as frontiers in precision therapy for colorectal cancer” was published in Advanced Cancer Research .
Li Z, Li X, Guo Q, Xu J, Zhu Y, et al. Malignancies of ISCs and their niche emerge as frontiers in precision therapy for colorectal cancer. Adv. Cancer Res. 2026(1):0004, https://doi.org/10.55092/acr20260004.
Advanced Cancer Research
Literature review
Not applicable
Malignancies of ISCs and their niche emerge as frontiers in precision therapy for colorectal cancer
14-Apr-2026