By
Elodie Vaz | Published on March 11, 2026 | 3 min read
Colorectal
cancer remains a major challenge in oncology. Immunotherapies targeting immune
checkpoints have transformed the management of many tumors, but their
effectiveness in this disease remains limited.
Most
patients present with so-called microsatellite-stable tumors, which are poorly
responsive to treatments targeting the PD-1/PD-L1 immune checkpoint axis. The
monoclonal antibodies currently used also have several limitations. Their large
size reduces their penetration into tumors, they can cause immune-related
adverse effects, and their production remains costly. In some aggressive forms
linked to chronic intestinal inflammation—such as colitis-associated colorectal
cancer—these treatments are often largely ineffective.
Testing
a new generation of miniature antibodies
In a
study published in eGastroenterology, researchers explored an innovative
approach based on mRNA-encoded nanobodies. Nanobodies are tiny single-domain
antibodies originally discovered in camelids and sharks. Their size—around 15
kDa compared with 150 kDa for a conventional antibody—allows them to penetrate
tumor tissues more efficiently while maintaining strong binding affinity.
However,
this small size also presents a drawback. Nanobodies are rapidly cleared by the
kidneys. To overcome this limitation, the researchers designed a “quadruple”
nanobody, combining four anti-PD-L1 nanobodies linked together by flexible
connectors. The goal was to increase the molecule’s circulation time while
preserving its advantages.
An
administration strategy inspired by mRNA vaccines
To
produce these nanobodies in the body, the team used a delivery technology based
on lipid nanoparticles containing modified mRNA. This strategy, popularized by
COVID-19 vaccines, enables cells to directly produce the therapeutic molecule.
The
researchers designed two versions: a monomeric form and a quadruple form. These
constructs were tested in several mouse models of colorectal cancer to evaluate
their antitumor efficacy.
Markedly
superior results with the quadruple nanobody
The
results show a clear difference between the two formats. While mRNA encoding a
single nanobody slightly slowed tumor growth, the quadruple version showed much
greater efficacy. It remained in the bloodstream about twice as long and
maintained higher therapeutic concentrations.
In
mice bearing sporadic colorectal tumors, four injections of lipid nanoparticles
significantly slowed tumor progression, with visible effects after the third
administration.
The
approach proved even more notable in models of colitis-associated colorectal
cancer, a situation in which conventional anti-PD-L1 antibodies generally fail.
The treatment reduced both the incidence and number of tumors.
Analyses
also showed remodeling of the tumor microenvironment: a decrease in
immunosuppressive myeloid-derived cells and tumor-associated macrophages,
alongside an increase in CD8+ T lymphocytes, which are essential for anticancer
immune responses.
Toward
new therapeutic strategies
Researchers
also observed that mRNA nanoparticles could directly influence immune cell
development. In vitro, they inhibit the differentiation of hematopoietic stem
cells into macrophages and reduce the expression of several immunosuppressive
markers.
This
preclinical study therefore suggests that mRNA-encoded anti-PD-L1 nanobodies
could represent a new immunotherapy approach for patients with colorectal
cancer. In the future, researchers are considering combination strategies
involving multiple nanobodies targeting different immune checkpoints or
combining them with chemotherapy or radiotherapy. Such approaches could open
the way to more effective treatments for colorectal cancers that are currently
resistant to immunotherapy.
Read
next: Meat and colorectal cancer: is the
risk underestimated?
About
the Author –
Elodie Vaz
Health journalist, CFPJ graduate (2023).
Élodie explores the marks diseases leave on bodies and, more broadly, on
human life. A registered nurse since 2010, she spent twelve years at patients’
bedsides before exchanging her stethoscope for a notebook. She now investigates
the links between environment and health, convinced that the vitality of life
cannot be reduced to that of human.
