Nature: Nanotechnology induces therapeutic immune responses to many types of tumors

On October 27, 2022, a study at the Ludwig Cancer Institute in New York developed a new nanotechnology that elicits a potent therapeutic anti-tumor immune response and demonstrated its efficacy
in mouse models of multiple cancers.
Led by supervisor Ralph Weichselbaum, investigator Wenbin Lin described the synthesis, mechanism of action and preclinical evaluation of the nanoparticle, which is loaded with a drug that activates a protein
that is critical for effectively inducing anti-cancer immunity.
This research overcomes a major technical obstacle to cancer treatment by protein-stimulating factors (sting) targeting the interferon gene and appears in the latest issue of natural nanotechnology.

Weichselbaum, co-director of the Chicago Center, said: "The nanoparticles developed in Lin's lab release a drug that targets macrophages that can activate a potent anti-tumor immune response and prolong survival in
mice with a variety of tumors.
" "When combined with radiotherapy and immunotherapy, they even help control 'cold tumors' that would otherwise be almost completely immune to
immune attack.
"

STING is part of a cellular sensing system for DNA fragments, which are produced by infections or cancer treatments that damage DNA, such as radiation therapy and some chemotherapy
.
Its activation promotes inflammation and drives immune cells such as macrophages and dendritic cells to process and deliver cancer antigens to T cells, helping to stimulate and direct immunity to attack tumors
.
Although STING is an important target for drug development, drug-like molecules that activate molecular sensors—called cyclic dinucleotides (CDNs)—have been plagued by poor bioavailability, low stability, and high toxicity because there is no way to specifically target them to tumors
.

To better target these drugs, Weichselbaum, Lin, Yang and colleagues encapsulated a CDN in
self-assembled spherical particles called nanoscale coordination polymers.
A single dose of nanoparticles, known as ZnCDA, due to the zinc ions they contained in their core, inhibited tumor growth in two mouse models of colon cancer: one was a solid tumor injected subcutaneously and the other was a liver metastases
.
ZnCDA also prolonged survival in b-cell lymphoma models, suppressed tumors in melanoma and prostate cancer models, and induced antitumor effects
in lung cancer models with an anti-STING activator.

Nanoparticles injected into the bloodstream tend to accumulate in tumors because the tumor-deformed blood vessels are leaky and the tumor's drainage system is poor
.
However, the researchers noted that the levels of ZnCDA aggregation in tumors were too high to be attributed to passive accumulation
alone.

Professor Lin said: "The accumulation of ZnCDA also activates STING in tumor vascular arrangement cells, which destroys the tumor vascular system, increases its leakability, and enhances the accumulation
of nanoparticles.
" "In a sense, nanoparticles can drive themselves to deliver drugs to malignant tissue, limiting toxicity and improving drug delivery efficiency
.
"

Macrophages in tumors exist in a biological gradient between two states or phenotypes: one is called M1, in which they stimulate an anti-tumor immune response and attack the cancer cells themselves – in effect, eating them; The other (M2), in this state they support cancer cell proliferation and survival
.

"We found that ZnCDA is particularly well absorbed by a subpopulation of macrophages, where it turns on gene expression programs that both push them to the M1 state and facilitate their submission of cancer antigens
to T cells," Yang said.

The researchers also tested the therapeutic potential
of ZnCDA against two tumors: pancreatic cancer and glioblastoma.
Both diseases are generally incurable and aggressive, characterized by cold tumors resisting radiotherapy and all available immunotherapies
.

The researchers found that a mouse model of pancreatic cancer became vulnerable to anti-PD-L1 immunotherapy under ZnCDA treatment, prolonging the survival time
of tumor-bearing mice.
When radiation therapy is added to the regimen, survival is even more prolonged
.
The researchers also showed that ZnCDA can cross the blood-brain barrier and accumulate in gliomas, where it attracts T cells into tumors and, when combined with anti-PD-L1 immunotherapy, prolongs survival in
treated mice.
This, combined with radiation therapy, prolongs survival
.

With a proof of concept in hand, the researchers are now poised to translate this nanotechnology into future clinical applications
.