By Ana Espino | Published on March 18, 2026 | 3 min readColorectal cancer (CRC) remains one
of the leading causes of cancer-related mortality worldwide. Despite advances
in surgery, chemotherapy, and targeted therapies,
metastatic CRC continues to
carry a poor prognosis. Therapeutic options remain limited after failure of
standard treatment lines.
Immunotherapy has transformed the
management of certain hematologic malignancies, particularly through CAR-T
cells. However, their efficacy in solid tumors, including CRC, remains limited
by several major barriers: an immunosuppressive tumor microenvironment, antigen
heterogeneity, stromal barriers, and the risk of “on-target, off-tumor”
toxicity.
This review, published in the Journal
of Clinical Oncology (2025), analyzes emerging antigen targets, recent
clinical trial results, and innovative strategies aimed at optimizing CAR-T
efficacy in CRC.
Which targets truly deliver?
The authors first outline the CAR-T
manufacturing process: leukapheresis, activation, genetic modification,
expansion, lymphodepletion, and reinfusion. Second- and third-generation CARs
incorporate costimulatory domains such as
CD28 or 4-1BB, improving persistence
and cytotoxic activity.
Several tumor antigens have been
evaluated.
CEA has been tested in a phase I
trial involving 10 patients with metastatic CRC. Seven patients achieved
disease stabilization, including two durable responses beyond 30 weeks.
Cytokine release syndrome (CRS) occurred in three patients, including one severe
case.
GUCY2C appears particularly
promising. In a phase I trial, the IM96 therapy demonstrated an
objective
response rate (ORR) of 26.3% and a disease control rate (DCR) of 73.7%, with a
median progression-free survival of 7 months at higher doses. The GCC19CART
product achieved an ORR of 40% in certain cohorts, with a reported median
overall survival of 22.8 months.
Other targets include
LGR5, a cancer
stem cell marker, as well as CDH17,
EpCAM, and
MSLN. Some approaches have shown
robust antitumor activity in preclinical models. However, severe pulmonary
toxicities have been reported with mesothelin-targeted CAR-T cells,
highlighting the challenge of antigen specificity.
The authors then detail biological
barriers. The CRC tumor microenvironment is enriched with regulatory T cells,
tumor-associated macrophages, and immunosuppressive cytokines such as
TGF-β. Antigen heterogeneity promotes
tumor escape, while the dense extracellular matrix limits cellular
infiltration.
To overcome these limitations,
several strategies are emerging:
“armored” CAR-T cells secreting IL-12, TRUCK
cells that modulate the microenvironment, bispecific or logic-gated CAR-T
designs to reduce off-target toxicity, and combinations with checkpoint
inhibitors such as pembrolizumab.
Patient selection may also improve
outcomes. Molecular subtypes such as
CMS1 (MSI-immune) appear more favorable
due to a more immunologically active microenvironment.
Personalization as the key to
performance
Metastatic colorectal cancer remains
a poor-prognosis disease despite current treatments. Major challenges include
tumor-induced immunosuppression, antigen heterogeneity, and potential toxicity.
The aim of this review was to assess
the potential of
CAR-T cells in CRC by analyzing targets, clinical outcomes,
and technological innovations. The data show
encouraging signals of efficacy,
particularly with GUCY2C, LGR5, and CDH17, along with generally acceptable
safety profiles in early-phase trials.
However, the results are derived
from early-phase, often non-randomized studies with small sample sizes.
Target-specific toxicities, particularly pulmonary events with certain
antigens, require careful antigen selection.
Future directions rely on optimizing
costimulatory domains, developing
allogeneic “off-the-shelf” approaches,
combination strategies, and refined molecular patient selection. Ultimately,
advanced CAR-T engineering could transform CRC management and pave the way for
truly personalized cellular immunotherapy in solid tumors.
Read next: Medicinal plants: an asset against colorectal cancer?
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
