Therapy administered by injecting a compound directly into tumors managed to convert immune cells already present there into active cells targeting cancer cells within the body. The findings from this new research are detailed in the journal ACS Nano.
This breakthrough redefines the role of tumors, transforming them from passive targets into sites where cell-based immunotherapy agents can be deployed immediately within the tumor rather than manufactured elsewhere.
Inside solid tumors, resident immune cells absorbed the therapeutic agent and began producing proteins that enabled them to recognize and assault cancerous cells.
Researchers based at the Korea Advanced Institute of Science and Technology (KAIST) demonstrated this transformation within tumors. Professor Ji-Ho Park and his team documented immune cells that shifted from a suppressed “bystander” status to an actively engaged “killer” state.
The effect manifested within the tumor mass itself, where immune cells typically unresponsive to the pressure exerted by cancer cells instead underwent sustained, targeted assault.
Because the alteration occurred locally, the outcome clearly delineated the scope of this method’s applicability and highlighted subsequent implementation hurdles.
Dense tumors in the lung, liver, or stomach often sequester immune cells at the periphery, where the cancer continues to advance.
The tough tissue structure, high internal pressure, and interwoven support fibers impede movement, causing even potent immunotherapeutic drugs to struggle with diffusion.
One review highlighted that merely 1–2% of CAR-T cells—T cells engineered to target malignancies—manage to reach the tumor core.
These physical and chemical obstacles help clarify why many immunotherapeutic strategies show great promise for blood cancers but diminish in efficacy when treating solid tumors.
In numerous tumors, macrophages—wandering immune cells that clear cellular debris and signal for reinforcements—can constitute nearly half the tumor’s mass at times.
Within the tumor, cancer cells can exert pressure on these cells to suppress inflammation, which weakens the engulfing response that could destroy the cancer.
When macrophages cease their attacks, they can even facilitate tumor growth by altering blood supply and silencing other immune system components.
Reprogramming the local workforce is crucial as it twists a fundamental weakness of solid tumors into a potential strength.
This treatment allowed the tumor’s own immune cells to learn to differentiate between malignant cells and healthy tissue.
Following uptake of the injected compound, macrophages inside the tumors started manufacturing a novel surface protein that flagged cancer cells for destruction.
The directives came from a transient genetic message contained within the drug, which guided the cells without making permanent alterations.
As these immune cells naturally traffic throughout solid tumors, this method bypassed the access barriers that limit many existing immunotherapies.
Lipid nanoparticles—tiny, fat-based capsules protecting the fragile genetic material—were essential for delivering the mRNA to the correct cells.
The coating facilitated cellular uptake of the package, followed by release of the mRNA where the cell’s machinery could read it and build the proteins.
By administering the drug directly into the tumors, the investigators steered the majority of the dose toward the macrophages already residing in that tissue.
Local delivery reduced the need for complex cell manufacturing, yet it tethered the approach to tumors accessible by clinicians.
The drug formulation also incorporated an intrinsic signal that alerted the immune cells that something was amiss, demanding an active response.
Once this signal was triggered, macrophages released chemicals that drew in other immune cells and maintained their focus on the tumor.
This additional stimulus was significant because tumors typically suppress such warning signals, allowing the cancer to thrive despite the presence of immune cells.
Intensifying immune signals within the tumor environment might also induce side effects such as swelling or pain, necessitating careful monitoring in future studies.
When tested on melanoma in mice—an aggressive, fast-spreading form of skin cancer—injections slowed tumor progression.
The reprogrammed macrophages attacked cancer cells directly and activated nearby immune cells, resulting in a higher accumulation of immune cells at the site.
In some mice, the immune response reached tumors that had never been injected, indicating an effect beyond the treated area.
Since physiological responses vary between mice and humans, the results warrant rigorous safety testing rather than immediate clinical rollout.
Cell therapy often takes weeks because labs must harvest, engineer, and expand cells before infusion.
A 2025 paper described a simpler method: programming macrophages in situ and letting the tumors complete the task.
“This study introduces a novel concept in immunotherapy where anti-cancer immune cells are generated directly inside the patient’s body,” stated Professor Park.
Even localized reprogramming of the immune system carries risks, as the modified macrophages could potentially target the wrong cells and cause harm to healthy tissue.
Antigen selection is critical because tumors share some surface markers with normal tissues, especially in organs like the liver.
This method also relies on mRNA, meaning the engineered receptor should degrade over time, though dosage schedules remain unclear.
Larger animal studies and thorough human preclinical trials will be needed for researchers to determine how this technique compares favorably to CAR-T therapy capabilities.
Repurposing tumor macrophages into engineered fighters and boosting local signaling could potentially make cell therapy more effective against hard-to-treat solid tumors.
Trials are now required in this field to verify safety, durability, and antigen specificity, as well as studies comparing injection sites across different cancer types.
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