The scale of the problem is substantial. As survival from cancer lengthens and treatment regimens grow more intense, kidney injury has emerged as a major clinical issue that can compromise both prognosis and quality of life. The review, led by Zixuan Chen and colleagues at Tongren Hospital, Shanghai Jiao Tong University School of Medicine, together with Hua Sun at the University of Iowa, catalogs how nearly every major class of anticancer therapy inflicts a distinct pattern of renal damage. Conventional chemotherapeutics, molecular targeted agents, immune checkpoint inhibitors, and immune cell therapies each attack the kidney through different biological routes, making ATRI not a single disease but a family of injuries requiring tailored solutions.

Cisplatin, a cornerstone of chemotherapy for decades, remains one of the most notorious offenders. The drug accumulates preferentially in renal proximal tubular epithelial cells, partly through the organic cation transporter 2, where it triggers oxidative stress, mitochondrial dysfunction, and tubular apoptosis. Even with standard preventive measures such as hydration, cisplatin-associated acute kidney injury remains clinically common, and when poorly managed it can progress to renal fibrosis and chronic kidney disease. Molecular targeted drugs behave differently. Inhibitors of the vascular endothelial growth factor pathway frequently cause proteinuria and hypertension by disrupting the delicate crosstalk between podocytes and glomerular endothelial cells, sometimes culminating in thrombotic microangiopathy. Fibroblast growth factor receptor inhibitors produce a strikingly different signature: hyperphosphatemia occurs in roughly 60 to 70 percent of patients, reflecting interference with the FGF23-FGFR axis and impaired renal phosphate handling.

The immunotherapy era has added entirely new injury patterns. Immune checkpoint inhibitors, by dismantling peripheral immune tolerance, can provoke T-cell attacks on renal antigens, most commonly manifesting as acute interstitial nephritis with an estimated incidence of 3 to 5 percent. Recent multicenter work incorporating immunophenotyping suggests these nephritides may include separable inflammatory subtypes that respond differently to glucocorticoids, underscoring the need for precision classification. Meanwhile, chimeric antigen receptor T-cell therapy introduces kidney injury through an even more circuitous route. Acute kidney injury after CAR-T therapy occurs in roughly 5 to 33 percent of patients, with a pooled incidence of about 19 percent, driven largely by cytokine release syndrome, capillary leak, hemodynamic instability, and tumor lysis rather than direct drug toxicity.

Current management of all these injuries is largely reactive. Clinicians rely on monitoring serum creatinine, adjusting doses, pausing treatment, or administering steroids when immune-mediated nephritis appears. Each approach carries a cost. Serum creatinine is a lagging indicator that can miss early tubular injury, and dose reduction, while often the most effective nephroprotective move, may compromise antitumor efficacy and limit regimen intensity. As combination regimens integrating chemotherapy, targeted therapy, immunotherapy, and cellular immunotherapy become standard, overlapping injury pathways and drug interactions are stretching current management paradigms to their limits. What is missing, the authors argue, is a strategy that actively preserves nephron structure and function without interfering with cancer treatment.

Enter mesenchymal stem cells, or MSCs, the most widely studied cell type in translational kidney protection. Rather than differentiating into renal parenchymal cells, MSCs act mainly as mobile secretory units, sensing tissue injury cues and releasing bioactive factors and extracellular vesicles that reshape the local microenvironment. Their renoprotective repertoire spans three dimensions. They secrete anti-inflammatory mediators such as TSG-6, prostaglandin E2, and interleukin-10 that dampen excessive immune activation. They release trophic factors including hepatocyte growth factor and VEGF that reduce tubular cell apoptosis, and in one particularly striking mechanism they deliver functional mitochondria to injured tubular cells through tunneling nanotubes, rapidly restoring bioenergetic capacity. They also suppress profibrotic signaling through the TGF-beta1 and Smad axis, limiting the scarring that follows sustained injury. These properties map most directly onto cisplatin-associated nephrotoxicity, where tubular stress, oxidative damage, and mitochondrial dysfunction dominate.

Yet MSCs face two formidable barriers in oncology. The first is delivery: after systemic infusion, only a small fraction of administered cells reach and persist within the kidney, constraining efficacy and increasing variability. Image-guided regional administration has shown promise in preclinical studies but remains unstandardized. The second, and thornier, barrier is oncologic safety. Because MSCs modulate immune responses and promote angiogenic signaling, their influence on the tumor microenvironment is a genuine theoretical concern, and the nature of that concern shifts with treatment context. In patients receiving checkpoint inhibitors, MSC immunoregulation might either resolve renal immune toxicity or blunt checkpoint efficacy. In those on VEGF pathway inhibitors, pro-angiogenic signals could theoretically counteract the antitumor mechanism itself. The authors suggest that acceptable risk may differ between curative-intent and palliative settings, with a more permissive calculus justified when renal preservation directly determines treatment continuity.

Renal progenitor and precursor cells represent a fundamentally different reparative philosophy: instead of modulating inflammation, they aim to replace lost epithelial cells and reconstruct nephron structure. Advances in induced pluripotent stem cell technology have enabled the generation of human iPSC-derived nephron progenitor cells expressing developmental markers such as SIX2 and WT1, capable of differentiating toward podocyte-like and tubular epithelial phenotypes. In mouse models of cisplatin-induced injury, transplanted progenitors localize to damaged regions, contribute to epithelial repair, and secrete trophic factors supporting recovery. Urine-derived precursor-like cells expressing SOX9-related programs offer a noninvasive, autologous sourcing route that sidesteps immune rejection. But the bar for clinical implementation is high: stringent control of cell purity, differentiation stage, genomic stability, and non-tumorigenicity is essential, particularly because chemotherapy and targeted therapies impose genotoxic pressures that could destabilize transplanted cells.

Exosomes, nanoscale vesicles carrying proteins, nucleic acids, and lipids, are emerging as the leading cell-free alternative. MSC-derived exosomes recapitulate many benefits of their parent cells while avoiding risks of live-cell administration such as microvascular trapping and uncontrolled proliferation. Their phospholipid bilayer protects cargo, their small size and low immunogenicity favor systemic delivery, and the absence of a complete cellular genome substantially reduces proliferation concerns. Exosomal microRNAs can modulate apoptosis and inflammatory signaling in recipient renal cells, while antioxidant enzymes mitigate reactive oxygen species. Yet the review issues a clear warning: exosomes are not inherently safer. Tumor-derived exosomes can promote immune evasion and therapeutic resistance, with reports in renal cell carcinoma showing that exosomes from drug-resistant cells carry elevated PD-L1. Even MSC-derived exosomes may carry pro-angiogenic or therapy-resistance-promoting cargo depending on source cell state and manufacturing conditions. Rigorous cargo profiling, standardized characterization under MISEV2023 guidance, and validation in tumor-bearing models are prerequisites before clinical advancement.

The path forward, the authors conclude, requires coordinated advances across engineering, delivery, clinical stratification, trial design, and manufacturing. Future cell products will likely be bioengineered rather than unmodified, with gene editing and controlled preconditioning creating context-responsive cells activated only within injured renal tissue. Kidney organoids are poised to become a transformative testing platform, recapitulating human renal injury in vitro and enabling higher-throughput screening of protective interventions. Clinically, the field must shift from reactive rescue to proactive, risk-adapted nephroprotection guided by novel biomarkers and integrated prediction models, and trials must adopt durable endpoints such as one-year estimated glomerular filtration rate slope and chronic kidney disease progression rather than short-term creatinine changes. For now, cell-based and cell-derived therapies remain emerging translational candidates rather than established treatments, but they offer something oncology has lacked: a conceptual framework for protecting the kidney without surrendering the cure.

Subject of Research: Cell-based and cell-derived renoprotective strategies for kidney injury caused by anticancer therapies

Article Title: Cell-based and cell-derived strategies for anticancer therapy-related renal injury: progress, challenges, and translational perspectives

Article References: Chen, Z., Xie, Y., Sun, H., & Liu, M. (2026). Cell-based and cell-derived strategies for anticancer therapy-related renal injury: progress, challenges, and translational perspectives. Holistic Integrative Oncology, 5(1), Article 61. https://doi.org/10.1007/s44178-026-00284-7

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00284-7

Keywords: onco-nephrology, acute kidney injury, mesenchymal stem cells, exosomes, renal progenitor cells, cisplatin nephrotoxicity, immune checkpoint inhibitors, CAR-T therapy, kidney organoids, cell therapy, renal fibrosis, extracellular vesicles

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