Natural killer cells are supposed to be the immune system’s first responders against cancer. They don’t need to be trained on a specific target the way T cells do. They recognize stressed or abnormal cells and destroy them on contact. But solid tumors have learned to shut them down, flooding the surrounding tissue with chemical signals that neutralize NK cells before they can do any damage.
A team at McGill University has now shown, in a peer-reviewed study published in EMBO Reports in May 2026, that blocking two specific protein phosphatases, PTPN1 and PTPN2, can reverse that shutdown. When the researchers silenced both proteins in human NK cells, the cells ramped up production of granzyme B and interferon-gamma, two molecules that punch holes in tumor cell membranes and trigger cancer cell death. The treated cells also became far more responsive to interleukin-2 (IL-2), a growth signal that drives immune activation, responding aggressively even at low concentrations.
The finding matters because it targets one of the most stubborn problems in cancer treatment: solid tumors that wall themselves off from the immune system and chemically disarm whatever immune cells manage to get inside.
What the McGill team actually showed
The researchers used both genetic silencing and pharmacological inhibition to knock out PTPN1 and PTPN2 in human NK cells grown in laboratory conditions. The dual approach was deliberate. Blocking just one of the two phosphatases produced modest effects; removing both created a much stronger response, as announced through the study’s institutional release on EurekAlert.
The enhanced IL-2 sensitivity worked through the JAK/STAT signaling pathway, which functions as a central amplifier for immune cell activation. In practical terms, this could matter for patients because IL-2 is already used in some cancer therapies but is limited by severe toxicity at the high doses currently required. NK cells that respond to lower IL-2 concentrations could potentially be activated with safer dosing.
Perhaps the most striking result involved TGF-beta-1, a molecule that solid tumors secrete in large quantities to suppress nearby immune activity. TGF-beta-1 is one of the most reliable weapons in a tumor’s defensive arsenal. The McGill team found that NK cells with PTPN1 and PTPN2 blocked resisted TGF-beta-1 suppression, maintaining their killing capacity in conditions designed to mimic the hostile interior of a solid tumor.
Building on a deeper evidence base
The McGill work did not emerge in isolation. It extends a line of research that has been building across multiple labs and immune cell types over the past several years.
In 2017, a team led by Robert Manguso at the Broad Institute used in vivo CRISPR screening to identify PTPN2 as a cancer immunotherapy target in T cells, publishing the results in Nature. That study established the basic principle: removing PTPN2 made immune cells more effective at killing tumors.
More recently, a 2023 Nature study demonstrated that ABBV-CLS-484, a small-molecule inhibitor targeting both PTPN2 and PTPN1, activated anti-tumor immune programs and showed signals of NK-cell pathway engagement alongside its primary effects on T cells and tumor cells. That compound, developed by AbbVie, is among the first drugs designed to hit both phosphatases simultaneously.
What the McGill team adds is direct, functional proof that the same logic applies to NK cells specifically. That distinction matters because NK cells and T cells kill cancer through overlapping but different mechanisms. NK cells act faster and don’t require prior antigen exposure, making them especially relevant for tumors that evade T-cell recognition by downregulating the surface markers T cells depend on.
The physical side of tumor defense
Chemical suppression is only half the story. Solid tumors also build physical barriers. They deposit dense layers of extracellular matrix proteins, particularly collagens, that form a stromal wall around the tumor mass. Research published in Science Advances has shown that these collagen structures directly suppress NK cell cytotoxicity, and that blocking collagen deposition in animal models increased NK-mediated killing.
This creates a two-layer defense: the physical wall keeps most immune cells out, and the chemical signals (TGF-beta-1, adenosine, and other immunosuppressive molecules) neutralize the few that get through. The PTPN1/PTPN2 strategy addresses the chemical layer. Whether combining it with approaches that break down the physical barrier would produce stronger results is a logical next question, but one that no published experiment has yet tested.
What this cannot tell us yet
All of the McGill data comes from human NK cell assays performed in controlled laboratory conditions. No animal tumor models, no patient-derived xenografts, and no human trial data have been reported. That gap is not a flaw in the research; it reflects where the work sits on the development timeline. But it is a critical caveat.
NK cells inside a living tumor face pressures that cell culture cannot replicate: low oxygen, fierce competition for nutrients, physical compression from dense stroma, and a constantly shifting mix of suppressive signals from tumor cells, regulatory immune cells, and cancer-associated fibroblasts. Benefits observed in vitro frequently shrink or disappear under those conditions.
Several specific unknowns stand out:
- Tumor type specificity. The published data do not identify which cancers might respond best. Tumors already infiltrated by NK cells that are being suppressed could be the clearest candidates, but “immune desert” tumors with very few NK cells present pose a different challenge entirely.
- Safety. PTPN1 and PTPN2 regulate signaling across many cell types, not just NK cells. Systemic inhibition could trigger autoimmune reactions or other off-target effects that only animal studies and carefully designed human trials can reveal.
- Dosing. No dosing regimens or long-term toxicity data for PTPN1/PTPN2 inhibitors in NK-focused models have been published.
- Interaction with existing therapies. How phosphatase inhibition would combine with CAR-NK cell therapies, which are already in early-phase clinical trials for solid tumors, or with checkpoint inhibitors that primarily boost T cells, remains unexplored.
Where NK-cell immunotherapy stands now
The broader field of NK-cell cancer therapy has been gaining momentum. CAR-NK cells, engineered to target specific tumor markers, have entered Phase I and Phase II clinical trials for several solid tumor types, with early results suggesting they may cause fewer severe side effects than their CAR-T cell counterparts. Companies including Fate Therapeutics and Nkarta have advanced candidates into the clinic.
The McGill findings occupy a different niche. Rather than engineering NK cells to recognize a specific target, the phosphatase inhibition approach aims to remove the brakes that tumors impose on NK cells that are already present or that have been delivered as therapy. In principle, the two strategies could complement each other: engineered NK cells that are also resistant to tumor-driven suppression.
But that combination remains hypothetical. No group has published results from pairing PTPN1/PTPN2 inhibition with CAR-NK therapy, ex vivo NK expansion protocols, or stromal remodeling agents in a single experimental model.
What the molecular map looks like
For researchers tracking the immunotherapy landscape, the McGill study adds PTPN1 and PTPN2 to a growing list of shared regulators across innate and adaptive immunity. The same molecular brakes that suppress T-cell responses inside tumors also suppress NK cells, which means drugs developed for one arm of the immune system may have broader utility than originally designed.
It also raises a practical question for ongoing clinical trials of compounds like ABBV-CLS-484: Are those trials measuring NK-cell function alongside T-cell endpoints? If not, they may be missing part of the therapeutic effect, or part of the toxicity profile.
For anyone following this space from outside the lab, the most grounded way to read the McGill findings is as a clearer map of the vulnerabilities inside a tumor’s immune-evasion machinery. The molecular switches are becoming better defined. The route from flipping those switches to durable responses in patients still has to be charted through animal models and, eventually, tightly controlled human trials. That work has not started yet for this specific NK-cell application, but the target is now well-defined enough to pursue.
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*This article was researched with the help of AI, with human editors creating the final content.
