This Week in Pathology — May 28, 2026

Welcome to This Week in Pathology. This week we're covering nine notable papers spanning oncology, advanced diagnostics and organ injury, and key updates in practice and global health. Let's dive in.

Our first theme this week is oncology, with three papers that explore the interplay between the tumor microenvironment, metabolic resistance pathways, and a successful new cellular therapy.

We begin in ovarian cancer, where a study in Science Translational Medicine addresses a key question: how does a tumor's own genomic instability shape its surroundings to promote drug resistance? [1] Investigators used single-cell analysis of high-grade serous ovarian carcinoma samples and found that tumors with high genomic instability activate an internal signaling pathway called STING. This, in turn, triggers the tumor cells to secrete WNT proteins. These WNT signals reprogram nearby fibroblasts, locking them into a specific lineage of cancer-associated fibroblasts, or myCAFs, which are marked by the protein POSTN. These POSTN-positive myCAFs create an immunosuppressive neighborhood by expanding regulatory T cells and exhausting cytotoxic CD8 T cells. This entire cascade ultimately limits the effectiveness of PARP inhibitors. The crucial insight is that this process can be intercepted. In preclinical models of ovarian and breast cancer, therapeutically blocking POSTN reinvigorated T cell activity, depleted the suppressive regulatory T cells, and successfully restored sensitivity to PARP inhibitor therapy. This work elegantly connects tumor-intrinsic genomics to the stromal response and identifies POSTN as a specific stromal checkpoint for overcoming therapy resistance.

Continuing with the theme of therapy resistance, a paper in Nature uncovers a fundamental metabolic mechanism that cancer cells use to repair their DNA. [2] The study focuses on homologous recombination, or HR, a key DNA repair process. In HR-proficient cancers, which are notoriously resistant to DNA-damaging agents, the researchers found a critical pathway dependent on the metabolite alpha-ketoglutarate. This metabolite is required for the function of an enzyme called TMLHE, which is the rate-limiting step in making carnitine. This newly synthesized carnitine is then essential for promoting histone acetylation at specific sites, which in turn facilitates HR-mediated DNA repair. This provides a direct link from a metabolic pathway—the alpha-ketoglutarate-carnitine axis—to the cell's ability to withstand chemotherapy. Clinically, the team found that in patients treated with DNA-damaging agents, high levels of either the TMLHE enzyme or acetylcarnitine correlated with worse progression-free survival. This discovery provides a new metabolic vulnerability; targeting this pathway could be a strategy for inducing an HR-deficient state in tumors, thereby making them sensitive to drugs like PARP inhibitors.

From mechanisms of resistance, we turn to a major therapeutic advance in hematologic malignancy. A phase 1 trial, also in Science Translational Medicine, reports on a new CAR T-cell therapy for relapsed or refractory multiple myeloma. [3] The product, named durcabtagene autoleucel, is a BCMA-directed CAR T-cell therapy manufactured using a rapid process designed to preserve T-cell stemness, a quality often lost during longer, traditional manufacturing. This is thought to reduce T-cell exhaustion and improve efficacy. For all 55 patients in the trial, the therapy was successfully manufactured with a median vein-to-vein time of just 24 days. The results were impressive. Across all dose levels, the overall response rate was 98%, with 55% of patients achieving a stringent complete response. Furthermore, 80% of evaluable patients became negative for minimal residual disease. The safety profile was manageable, with no unexpected findings or delayed neurotoxicity. Transcriptomic analysis confirmed that the final cell product did indeed preserve a desirable stem-like phenotype. Based on these strong results, a phase 2 trial is already underway.

Our next theme explores how advanced diagnostics and cellular engineering are reshaping our understanding and treatment of organ injury.

First, a report in Modern Pathology tackles the limitations of standard two-dimensional histology in prostate cancer. [4] Pathologists diagnose and grade prostate cancer from thin sections, but these slices can't capture the full three-dimensional network of glands. The authors hypothesized that these 3D architectural features hold prognostic information. Using Open-Top Light-Sheet microscopy on archived prostatectomy samples, they developed a computational framework called GlaSkeN. This AI-powered tool uses deep learning to segment glandular structures in 3D and then extracts quantitative features like branching angles and curvature. The key finding: these 3D architectural features were significantly associated with 5-year biochemical recurrence-free survival in two separate cohorts. Importantly, in a multivariable analysis, the prognostic power of the 3D features remained significant even after accounting for standard clinicopathological variables. This suggests that analyzing 3D gland architecture could provide valuable prognostic information to complement current grading systems.

From 3D tissue imaging, we move to single-cell genomics to understand organ injury in the kidney. A study in Science Translational Medicine investigated the pathophysiology of cholesterol crystal embolism, a dangerous complication of advanced atherosclerosis that can cause acute kidney injury. [5] Using a mouse model, researchers performed single-cell transcriptomics on the kidney after an embolic event. This created a detailed map of the cellular response, revealing widespread changes across 17 different kidney cell types. Analysis of cell-cell interactions pinpointed two specific signaling pathways as central to the resulting inflammation and vascular injury: the CCL-CCR5 and MIF-CD74 axes. The relevance to humans was confirmed by finding CD74-positive staining near cholesterol clefts in kidney biopsies from patients with the condition. The researchers then tested this insight therapeutically. Pharmacological inhibition of CCR5 with maraviroc or CD74 with milatuzumab reduced vascular thrombosis and tissue damage in the mouse model. Critically, the treatment was still effective even when delayed for two hours after the embolism, highlighting these pathways as promising therapeutic targets for necroinflammation in this setting.

Broadening the scope from a single organ to the entire hematopoietic system, a paper in Nature introduces the concept of inflammatory memory within stem cells. [6] It’s long been known that inflammation can have lasting effects, but the cellular mechanism has been unclear. The researchers identified a distinct subset of human hematopoietic stem cells, which they termed HSC-iM, for 'HSC inflammatory memory'. These cells, which retain a molecular memory of previous inflammatory stress, are transcriptionally and epigenetically different from other HSCs. They tend to be quiescent and have restrained output. This HSC-iM program was found to be enriched in stem cells from individuals across a range of conditions, including recovery from COVID-19, sickle cell disease, aging, and clonal hematopoiesis. This memory isn't just a historical record; it has functional consequences. The pro-inflammatory program can be passed down to differentiated immune progeny. Most strikingly, in a large population cohort, enrichment of this HSC-iM signature in circulating blood cells was associated with a heightened risk for all-cause mortality, underscoring the profound clinical relevance of this newly identified stem cell state.

Finally in this section, a study from The New England Journal of Medicine reports on an attempt to reverse organ damage in heart failure using cellular engineering. [7] The trial tested Biologic Ventricular Assist Tissue, or BioVAT, which is an engineered heart muscle patch made from cardiomyocytes derived from allogeneic induced pluripotent stem cells. This phase 1-2 study enrolled patients with heart failure and a left ventricular ejection fraction of 35% or less. The patches were implanted onto the heart, and patients received immunosuppression. The interim results at 3 months for 12 patients who received the maximal dose are presented.

Results

There were signs of efficacy. The target heart-wall thickness increased by a mean of 4.5 millimeters, the left ventricular ejection fraction increased by 3.9 percentage points, and patient-reported quality of life scores also improved. However, the safety profile is a major concern. All patients had at least one adverse event. During the study, three patients died, one required a heart transplant, and two needed a mechanical left ventricular assist device. While the early efficacy signals are encouraging, the high rate of adverse events tempers enthusiasm and underscores that this is very early-stage research warranting longer-term follow-up.

Our final theme covers important updates for clinical practice and global health.

First, from the Archives of Pathology & Laboratory Medicine, the College of American Pathologists, in collaboration with the Association of Directors of Anatomic and Subspecialty Pathology, has released an update to its guideline on reducing interpretive diagnostic errors. [8] Following a systematic literature review, an expert panel established two strong recommendations and four good practice statements. The core message is a strong recommendation that anatomic pathologists should implement procedures for the review of pathology cases to detect and correct potential interpretive errors, with the goal of improving patient outcomes. This update reinforces the critical importance of quality assurance and peer review systems in our daily practice.

And finally, a clinical review in The New England Journal of Medicine provides a concise update on the leishmaniases, a group of diseases caused by the protozoan parasite Leishmania. [9] The review highlights key epidemiologic trends: cases of cutaneous leishmaniasis are increasing, especially in the Eastern Mediterranean, while the global prevalence of the life-threatening visceral form is decreasing. On the diagnostic front, the field has largely shifted to using molecular methods on tissue samples, which also allows for species identification. Treatment remains a challenge due to limited drug options, but the use of combination therapies for visceral leishmaniasis is noted as a recent advance. Preclinical work on two human vaccines is also underway.

If you only have time for one paper this week, make it the Nature paper on hematopoietic stem cell inflammatory memory. [6] It identifies a distinct stem cell subset that remembers past inflammation, linking it to clonal hematopoiesis, aging, and a higher risk of all-cause mortality, providing a new framework for understanding long-term health outcomes after inflammatory stress.

Here are the key takeaways from this week in Pathology.

First: In ovarian cancer, tumor genomic instability can drive stromal reprogramming into an immunosuppressive microenvironment via the STING-WNT-POSTN axis, contributing to PARP inhibitor resistance. Targeting POSTN is a promising strategy. [1]

Second: A new rapid-manufacture CAR T-cell therapy for multiple myeloma, durcabtagene autoleucel, showed a nearly 100% overall response rate in a phase 1 trial, with a favorable safety profile and preservation of T-cell stemness. [3]

Third: Three-dimensional architectural analysis of prostate glands using AI can identify features that predict biochemical recurrence, adding prognostic value beyond standard 2D histopathology and clinical variables. [4]

Fourth: Following inflammatory stress, hematopoietic stem cells can form a quiescent 'inflammatory memory' subset. The enrichment of this program in blood cells is associated with a higher risk for all-cause mortality, providing a cellular basis for the long-term consequences of inflammation. [6]

And Fifth: An updated guideline from the College of American Pathologists strongly recommends that anatomic pathologists implement procedures for reviewing cases to detect and correct potential interpretive errors. [8]

That's your roundup for This Week in Pathology. The full transcript and references are available on the episode page in your AudioScholar library. This is an AI-curated summary — for clinical decisions, always consult primary sources and current guidelines. See you next week.