The research team, led by investigators at Capital Medical University in Beijing, combined bioinformatics, flow cytometry and multiplex immunohistochemical staining to chart where LAIR1 is expressed in human gliomas. The answer was unambiguous: LAIR1 is found predominantly on glioma-associated microglia and macrophages, collectively known as GAMs. Patients whose tumours harboured high numbers of LAIR1-expressing GAMs survived significantly less long than those with lower infiltration, establishing the receptor as a marker, and potentially a driver, of aggressive disease.

To test whether LAIR1 merely accompanies poor outcomes or actively causes them, the researchers turned to genetically engineered mice lacking the Lair1 gene. In orthotopic glioma models, in which tumours are implanted within the brain itself, LAIR1 deficiency substantially reduced tumour burden. The effect was traced to the behaviour of the immune cells rather than the tumour cells: when LAIR1 was absent, GAMs displayed enhanced tumoricidal activity in laboratory assays, engulfing tumour cells more readily and mounting stronger anti-tumour responses.

Single-cell and bulk RNA sequencing of LAIR1-high GAMs revealed a strongly immunosuppressive phenotype. These cells expressed molecular programmes associated with dampened T-cell responses, a hallmark of the glioma microenvironment that has repeatedly frustrated immunotherapy efforts. Notably, the team found that LAIR1-high GAMs were linked to the CD47-SIRPα axis, a well-known ‘don’t eat me’ signalling pair in which tumour cells display CD47 on their surface to engage SIRPα on macrophages and shut down engulfment. In mouse models, tumours rich in LAIR1-high GAMs were resistant to anti-PD-1 checkpoint blockade, connecting this receptor to the clinical failure of immunotherapy in brain cancer.

The mechanistic heart of the study concerns a protein called MYH9, the heavy chain of non-muscle myosin IIA. Myosin II motors are well established as physical enablers of phagocytosis: they generate the contractile force needed for a macrophage to extend its membrane around a target and pull it inside. Previous work has shown that myosin II activity must be precisely regulated at the phagocytic synapse, and the new findings place MYH9 at the centre of LAIR1’s suppressive circuit in GAMs.

Using co-immunoprecipitation, PCR arrays, molecular dynamics analysis and CRISPR/Cas9 gene editing, the researchers pieced together the pathway step by step. Collagen I, an abundant component of the glioma extracellular matrix, activates LAIR1 on the surface of GAMs. Once engaged, LAIR1 recruits and activates the phosphatase SHP2, which removes a phosphate group from MYH9 at the amino acid serine 1943. This dephosphorylation event has far-reaching consequences: it prevents the recruitment of USP22, a deubiquitylating enzyme that would otherwise stabilise MYH9 by stripping off ubiquitin tags that mark proteins for destruction.

With USP22 blocked from acting on MYH9, the myosin protein loses its protective deubiquitylation and is degraded. The same logic applies to HIF1α, a transcription factor that USP22 also stabilises and that supports the pro-tumour behaviour of macrophages. The net result is that the phagocytic machinery of the GAM is dismantled: the cell can no longer build the contractile apparatus needed to engulf glioma cells, and the immunosuppressive character of the microenvironment deepens. In this way, a collagen-rich tumour matrix actively disarms the very immune cells that patrol it.

The study’s experimental design was unusually comprehensive. Beyond Lair1-deficient mice, the team used engineered BV2 microglial cell lines, bone marrow-derived macrophages and GAMs isolated directly from patients treated at Beijing Tiantan Hospital. RNA sequencing and targeted PCR arrays defined the transcriptional landscape, while molecular dynamics simulations supported the structural basis of the SHP2-MYH9 interaction. Raw sequencing data were deposited in the NCBI Sequence Read Archive, and the work was approved by the Ethics Committee of Beijing Tiantan Hospital, adding translational weight to the preclinical findings.

The therapeutic implications are considerable. LAIR1 belongs to the LILRB family of inhibitory immune receptors, several of which are being pursued as ‘ innate immune checkpoints’ in cancer. LAIR1 itself has attracted attention because it binds collagen domains and has been implicated in T-cell exhaustion in collagen-dense tumours, in acute myeloid leukaemia development, and in resistance to T-cell attack in hepatocellular carcinoma. Antibody blockade of LAIR1 and LAIR1-directed CAR T cells have already shown enhanced anti-tumour responses in preclinical models, suggesting that a pharmacological toolkit for targeting this receptor is beginning to take shape.

What distinguishes the new work is that it defines a complete, testable signalling axis, from extracellular collagen through LAIR1 and SHP2 to USP22, MYH9 and HIF1α, and ties each link to the functional outcome of phagocytosis in glioma-associated immune cells. If LAIR1 can be safely blocked in patients, the brake on GAM engulfment could be released, potentially converting the largest immune population in glioma from a tumour ally into an attacker. Such a strategy might also sensitise tumours to existing checkpoint inhibitors, addressing the anti-PD-1 resistance that the study directly documents. For a disease in which median survival has barely moved in decades, a molecular switch that reprograms the tumour’s own microenvironment offers a genuinely new line of attack, and one that researchers can now pursue with a clear mechanistic map in hand.

Subject of Research: LAIR1-mediated suppression of phagocytosis in glioma-associated microglia and macrophages

Article Title: LAIR1 suppresses phagocytosis via SHP2/USP22-mediated MYH9 degradation in glioma-associated microglia/macrophages to drive immunosuppression

Article References: Wang, Z., Sun, Q., Li, C., Sun, T., He, Z., Wang, Y., Li, R., Lin, X., Jasiulionis, M. G., Ji, N., Zhang, Y., & Xu, H. (2026). LAIR1 suppresses phagocytosis via SHP2/USP22-mediated MYH9 degradation in glioma-associated microglia/macrophages to drive immunosuppression. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03617-5

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03617-5

Keywords: glioma, LAIR1, phagocytosis, microglia, macrophages, SHP2, USP22, MYH9, CD47-SIRPalpha, immunosuppression, immunotherapy resistance, tumour microenvironment

The numbers behind the review are sobering. Between 1990 and 2021, the global burden of chronic kidney disease driven by type 2 diabetes nearly doubled, reflecting an increase of roughly 80 to 90 percent. In the United States, annual all-cause healthcare costs for an insured patient with diabetic kidney disease climb from about 30,000 dollars in early stages to approximately 119,000 dollars as the disease advances. These figures capture more than economic strain; they reflect a disease whose cellular and molecular underpinnings remain only partially mapped, and whose progression is rarely reversible once structural injury takes hold. The authors of the review, Grace LeBleu and Fawaz G. Haj, contend that aberrant tyrosine phosphorylation—a reversible chemical switch that controls how cells respond to insulin, growth factors, and inflammatory cues—is a hallmark of diabetic kidney injury, and that the enzymes which remove these phosphate marks deserve far greater therapeutic attention.

Tyrosine phosphorylation is governed by a tug of war between two enzyme families: protein tyrosine kinases, which add phosphate groups to proteins, and protein tyrosine phosphatases, which remove them. While kinases have long been celebrated drug targets, phosphatases were for years dismissed as undruggable, largely because their catalytic pockets are highly conserved and positively charged, making selective inhibition difficult. The human genome encodes more than 100 phosphatase genes, of which 38 are classical phosphatases that specifically target phosphotyrosine residues—21 of the receptor-type and 17 of the non-receptor-type. The review systematically catalogs the evidence linking each of these 38 enzymes to diabetic kidney disease, ranging from directly established contributors to those implicated only indirectly or not at all.

Among the most firmly established is PTP1B, encoded by the PTPN1 gene. Discovered in the late 1980s and early 1990s as a negative regulator of insulin signaling, PTP1B dephosphorylates the insulin receptor and dampens downstream cascades. In podocytes—the specialized cells whose foot processes form the kidney’s filtration barrier—PTP1B knockdown stabilizes the cytoskeleton and preserves insulin signaling under high-glucose conditions. Recent work identified the cytoskeletal protein alpha-actinin-4 as a PTP1B substrate in insulin-stimulated podocytes, linking the enzyme directly to podocyte motility. In mouse models, global PTP1B deletion markedly attenuates glomerular injury and reduces albuminuria without major changes in blood glucose or pressure, while podocyte-specific deletion or pharmacological inhibition preserves podocyte architecture and blunts glomerular basement membrane thickening. Notably, PTP1B expression has been reported to be elevated in glomerular biopsies from patients with diabetic kidney disease, lending human relevance to the animal findings.

SHP2, the product of PTPN11, has emerged as another central player. In podocytes exposed to high glucose, SHP2 expression rises alongside increased endoplasmic reticulum stress, activation of the inflammatory transcription factor NF-κB, and heightened cell motility; silencing the enzyme prevents these changes. In diabetic mice, elevated SHP2 phosphorylation appears in macrophages, glomeruli, and podocytes, and podocyte-specific genetic deletion or pharmacological inhibition preserves renal function, lowering albuminuria and blood urea nitrogen. Immunohistochemical analysis of renal biopsies from patients with diabetic kidney disease reveals elevated phosphorylated SHP2 at a key activating site, and small-molecule inhibitors such as SHP099 and PHPS1 have shown renoprotective effects in rodent models of both type 1 and type 2 diabetes. SHP1, encoded by PTPN6, tells a similar story: hyperglycemia raises its expression in podocytes, disrupting insulin signaling and promoting apoptosis, while podocyte-specific deletion of SHP1 reduces albuminuria and reverses features of disease progression, apparently by restoring SUMOylation of the slit diaphragm protein podocin.

The review also spotlights endothelial and podocyte receptor-type phosphatases with distinctive renal roles. VEPTP, encoded by PTPRB, is largely restricted to endothelial cells in the adult kidney, where it dephosphorylates the angiopoietin receptor TIE2. Hyperglycemia, osmotic stress, and hypoxia all increase VEPTP expression, and inducible genetic deletion in diabetic mice improves glomerular filtration rate, reduces matrix accumulation, and preserves podocyte integrity—although an antibody-based inhibition approach alone failed to improve albuminuria, hinting that endothelial protection must be paired with therapies addressing the filtration barrier itself. CD148, encoded by PTPRJ, dephosphorylates growth factor receptors including VEGFR2 and EGFR, and an agonistic anti-CD148 antibody that boosts the enzyme’s activity attenuated albuminuria and mesangial expansion in diabetic mice. GLEPP1, encoded by PTPRO, sits on the apical surface of podocytes, and its deletion produces structurally abnormal foot processes, hypertension, and reduced filtration capacity, while its expression is diminished in sclerosed glomeruli from patients with diabetic kidney disease.

Beyond these established players, the review traces a broader web of phosphatases implicated in diabetes and renal pathology. TCPTP dephosphorylates the insulin receptor non-redundantly with PTP1B; its overexpression via gene therapy ameliorated albuminuria and renal morphology in diabetic mice, and its levels are reduced in patients with early-stage diabetic kidney disease. PEZ, or PTPN14, modulates the Hippo pathway through YAP and drives inflammatory and fibrotic signaling via TRIP6, with elevated expression detected in diabetic glomeruli and patient kidneys. RPTPζ serves as a receptor for interleukin-34, recruiting macrophages to injured tubules, while RPTPγ functions as a carbon dioxide and bicarbonate sensor in proximal tubular cells and rises in the serum as diabetic kidney disease progresses. Immune-associated phosphatases such as CD45, PTPN22, and HePTP connect renal inflammation and fibrosis to leukocyte signaling, and a cluster of enzymes including LAR, RPTPε, RPTPσ, and PTP-MEG2 modulate insulin signaling in muscle, liver, and adipose tissue, with several genetic variants linked to type 2 diabetes risk.

What makes the moment ripe for phosphatase-directed therapy is a confluence of pharmacological progress. Current standard care—RAAS blockade with ACE inhibitors or angiotensin receptor blockers, SGLT2 inhibitors validated by the DAPA-CKD, EMPA-KIDNEY, and CREDENCE trials, GLP-1 receptor agonists demonstrated in the FLOW trial, and the nonsteroidal mineralocorticoid receptor antagonist finerenone—slows disease but rarely reverses injury. Combination regimens are increasingly viewed as the path forward, and phosphatase modulators could slot into this framework as complementary agents. SHP2 inhibitors have already advanced through phase I, II, and III oncology trials, while the allosteric inhibitor SHP099 reduced albuminuria and blood urea nitrogen in diabetic mouse models. PTP1B inhibitors including ertiprotafib and trodusquemine reached clinical trials for type 2 diabetes and obesity, and an antisense oligonucleotide, IONIS-PTP-1BRx, lowered HbA1c and body weight in overweight patients with type 2 diabetes. VEPTP inhibition with AKB-9778 progressed to phase II trials for diabetic retinopathy, where patients showed a modest reduction in urinary albumin-to-creatinine ratio.

Novel modalities are expanding the toolbox further. Allosteric inhibitors that bind sites outside the conserved catalytic pocket promise improved selectivity, bivalent ligands engage both active and adjacent sites, and targeted protein degradation via PROTAC technology—exemplified by the SHP2 degrader SHP2-D26—offers a route to eliminate rather than merely inhibit the enzyme. Artificial intelligence and machine learning workflows have already been applied to PTP1B and SHP2 inhibitor discovery, helping overcome the historical barrier of conserved catalytic pockets by identifying selective binding modes and optimized physicochemical properties. The authors emphasize that pharmacological modulation need not mean inhibition in every case: for CD148, whose activity appears protective, an activation strategy is the goal, illustrating the nuanced directionality of phosphatase drug development.

The review’s bottom line is a call to translational action. Diabetic kidney disease remains the leading cause of end-stage renal failure, and existing therapies, however effective at slowing decline, rarely restore lost function. Classical protein tyrosine phosphatases sit upstream of the insulin, inflammatory, oxidative stress, and cytoskeletal cascades that converge to destroy the kidney in diabetes, and several are now pharmacologically tractable. The challenge ahead lies in bridging preclinical promise to clinical reality—defining cell-type-specific roles, establishing context-dependent effects in human disease, and testing phosphatase-targeted agents in combination with established therapies. If that bridge can be built, enzymes once written off as undruggable may finally deliver the precision treatments that patients with diabetic kidney disease have been waiting for.

Subject of Research: The roles of classical protein tyrosine phosphatases in the pathogenesis and treatment of diabetic kidney disease

Article Title: The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications

Article References: LeBleu, G., & Haj, F. G. (2026). The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications. Journal of Biomedical Science, 33(1), Article 89. https://doi.org/10.1186/s12929-026-01282-7

Image Credits: AI Generated

DOI: 10.1186/s12929-026-01282-7

Keywords: diabetic kidney disease, protein tyrosine phosphatases, PTP1B, SHP2, podocytes, insulin signaling, renal fibrosis, SGLT2 inhibitors, phosphatase inhibitors, drug discovery, chronic kidney disease, inflammation