Frontiers in Oncology: There will be a radical cure for advanced cancer, and new anti-cancer technologies may be able to eradicate malignant tumors!

When cancer cells were injected again into cured mice for 60 days, no new tumors were observed
.
The study, titled "Eradication of tumors and development of anti-cancer immunity using STINGa targeted by pHLIP," has been published in the journal Frontiers in Oncology (Figure 1).

Figure 1 Research results (Source: Frontiers in Oncology)

The researchers eradicated malignancy in mice by combining immunotherapeutic agents with molecular delivery systems that target tumor acidity
.
The method links an immunotherapy agent of a STING (STimulator of InterferoN Gene) agonist to an acid-seeking molecule of another pHLIP.
®
The pHLIP molecule targets the highly acidic nature of cancerous tumors, delivering their immunotherapy cargo directly to cells
in the tumor microenvironment.
Once released, STING agonists stimulate the body's innate immune response to fight tumors
.

pHLIP is able to specifically target STING agonists to tumor cells, not only cancer cells, but also dormant immune cells within tumors, significantly increasing their potency
.
PHLIP is a peptide (chain of amino acids) derived from bacteriorhodopsin, a membrane protein
that enables certain single-celled organisms to convert light into energy.

Yana Reshetnyak, author of this study, said: "STING agonists are an important class of immunomodulators, and studies have shown that they often do not work alone and need to be targeted in some way, and using pHLIP to target tumors through its acidic targeting can successfully search for a variety of different cell types in the tumor microenvironment and achieve synergistic effects and quite significant therapeutic effects
.
" ”

Figure 2 Research process (Source: Frontiers in Oncology)

■ The untreated tumor (upper left) is highly acidic, as indicated by its response to fluorescent dyes (upper right).

A few days after treatment (lower left), the tumor stroma is destroyed and the pH is reduced (lower right).

The researchers say that just a single dose of the combination of pHLIP STING agonists could eradicate colorectal cancer and even large, advanced tumors
in mice.
The treated mice also developed long-lasting immunity, allowing their immune systems to recognize and fight cancer
long after the tumor had disappeared.
While the researchers emphasize that successful cancer-fighting results in mice do not represent complete replication in humans, the major discovery could test the safety and efficacy of cancer patients, setting the stage for
potential clinical trials.

Targeted immunotherapy

Immunotherapy is an emerging approach
to fighting cancer.
Tumor cells evade the immune system, causing the tumor to spread
further.
In some cases, tumor cells do this by expressing proteins that act as immune stealth devices, tricking the immune system into thinking that tumor cells are normal, natural cells, and immunotherapy aims to defeat these invisible devices
.

One way to remove tumors is to use immunosuppressants, which are effective in treating many types of cancer
.
But these drugs are not effective
for all tumors.
While they work well on immuno-"hot" tumors with a lot of inflammation, they work less
well on "cold" non-inflammatory tumors.
STING agonists are a means of turning cold tumors into hot tumors, making them more susceptible to immune
responses.
They do this by causing cells to release interferon, a red flag protein that alerts the immune system to foreign invaders
.

The researchers showed that the molecule can be attached to the pHLIP peptide portion of the cell membrane, a "transport" process that helps doctors see more clearly the tumor's diagnostic agent, or immunomodulators
such as STING agonists.
pHLIP only enters cells in a highly acidic environment, they can target tumor cells and do not affect healthy cells
.

New anti-cancer technology can cure tumors

To test the effectiveness of targeting through pHLIP increases STING agonist activity, the researchers injected 20 mice with small colon tumors with a single pHLIP STING antagonist
.
Within a few days, the tumors of 18 mice disappeared
completely.
The team also treated 10 mice
with larger tumors with a single injection.
Seven of the mice had tumors eradicated
.
Ten mice in the control group received injections
of non-targeted STING agonists.
Despite the slow growth of tumors for a short period of time, tumors remained
in all mice.

The treatment also stimulated the immune memory
of the treated mice.
When the researchers injected cancer cells into mice that had been eliminated for 60 days, no new tumors
grew in those mice.
This suggests that once the immune system is ready to attack tumor cells, immune memory continues to attack tumor cells without the need for additional treatment
.

The high tumor eradication rate is encouraging, but even more surprising is that pHLIP STING agonists can target many types of tumor cells
.
Tumors don't just contain cancer cells, many patients also have a stroma, a coating that is non-cancerous and forms a physical and chemical barrier that protects the tumor from the
human immune system.
When studying the structure of the tumor several hours after the pHLIP STING agonist injection, the researchers found a significant reduction in
stromal cells.

"The stroma is essentially disrupted, regulating the behavior of multiple cells in the tumor stroma as well as the cancer cells themselves, which means synergistically inducing interferon signaling in multiple cell types and treating the tumor
as a whole," the researchers said.
This is the advantage of using acidity as a target: the ability to target the entire tumor, not just certain cell types
.
”

Although this trial is currently based on the data of animal models, but good efficacy brings infinite hope to researchers, the combination of targeted technology and immunotherapy, there is an excellent effect of 1+1>2, which can provide a safe, effective way to remove cancer cells, for the treatment of a variety of solid tumor cancer, it is expected to provide a new high-efficiency treatment method, to a certain extent to prevent cancer recurrence immune effect
.
The research is supported by the National Institutes of Health, and the technology in the trial has attracted the attention of many investors, and the commercialization of pHLIP technology is just around
the corner.

Original source:

Anna Moshnikova， et al.
Eradication of tumors and development of anti-cancer immunity using STINGa targeted by pHLIP.
Frontiers in Oncology， 2022.