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TCR-engineered T cells have shown limited efficacy in part due to the absence of co-stimulation leading to limited accumulation in solid tumors. The authors here show engineering the CD8β coreceptor with an intracellular CD28 domain enhances cytokine production, persistence, and tumor control in vivo independent of tumor-associated co-stimulatory ligand encounter.

Ribas and colleagues report the results of a phase 2 clinical trial of neoadjuvant PD-1 blockade in patients with surgically resectable desmoplastic melanoma.

Here, the authors show that pre-infection gastrointestinal microbial composition predicts parasite levels in rhesus macaques infected with P. fragile and humans infected with P. falciparum in a controlled human malaria infection (CHMI) study.

Integrating computational analyses of T cell exhaustion and mitochondrial fitness atlases with in vivo CRISPR screens has identified KLHL6 as a dual-negative regulator of both exhaustion differentiation and mitochondrial dysfunction, highlighting its potential as a target to enhance anti-tumour immunity.

Here, the authors show that base editing of CD33 and gamma globin genes in HSPCs results in the long-term engraftment of dual edited cells along with HbF reactivation and GO resistance in mice and nonhuman primates.

Basal Pancreatic Ductal Adenocarcinoma (PDAC) is more aggressive than the classical subtype of pancreatic cancer. Here the authors report that RNA-binding protein LIN28B and its target HMGA2 drive basal PDAC pathogenesis by reducing PP2A methylation and activity, resulting in enhanced protein synthesis and aggressive features.

The thymus is sensitive to acute insults including infection, as well as to injury from chemotherapy and myeloablative conditioning before hematopoietic cell transplantation. Here, Granadier et al. describe a role for IL-18 in limiting thymic regeneration by stimulating NK cells, which then target thymic epithelial cells.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Combination immunotherapy approaches might be effective in inducing sustained control of HIV by slowing rebound and improving CD8⁺ T cell responses.

Toghani, Gupte et al. identify semaphorin 4A as a cell-extrinsic factor that protects myeloid-biased hematopoietic stem cells from inflammaging, mainly produced by their progeny—neutrophils—and acting via a negative feedback loop.

Antibody immunoprophylaxis for HIV-1 will require effective concentration of biologics at mucosal sites of exposure for effectivity. Here the authors show that infused Fc-modified VRC01LS antibody has increased levels in blood, in the female genital tract and male rectal tissue, compared to native antibody VRC01. VRC01LS is detectable for more than year at the sites of sexual HIV transmission.

Breastfeeding is inversely associated with cardiometabolic disease; however, the metabolic pathways underlying these associations remain largely unknown. Here, the authors show plasma metabolite profiles in mid-life associated with breastfeeding duration, which is also linked to CVD and T2D risk.

Ghajar and colleagues report that astrocyte-deposited laminin-211 promotes the quiescence of disseminated tumor cells in the brain, in a manner dependent on the cytoplasmic sequestration of YAP by dystroglycan.

Mitochondrial DNA heteroplasmy associates with context-specific nuclear CpG methylation, supported by a cell model. Heteroplasmy–CpG scores relate to mortality and cardiovascular risk, though direction and mechanisms remain unclear.

Vaccines inducing mucosal immunity may provide better protection from respiratory viruses. Here, Ykema et al. demonstrate the utility of a bivalent, mucosally delivered nanostructured lipid carrier-replicon vaccine for induction of mucosal and systemic immunity and protection against morbidity and mortality from H5N1 and H7N9 influenza.

Klein and colleagues characterize 04_A06, a new V_H1-2-encoded broadly neutralizing antibody that has marked breadth and potency against extended multiclade HIV-1 pseudovirus panels and can maintain full viral suppression in HIV-1-infected humanized mice.

The MOUNTAINEER phase 2 trial demonstrated the efficacy and safety of tucatinib (HER2-targeted TKI) and trastuzumab (anti-HER2 antibody) in patients with HER2 + , RAS wildtype unresectable or metastatic colorectal cancer that had progressed on chemotherapy, resulting in the approval of the regimen. Here, the authors report the updated analysis of the MOUNTAINEER trial.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Using data from the CoVPN 3008 study, the authors show that the neutralizing antibody correlate of risk holds in people living with HIV. However, the nAb correlate was weaker and shorter-lived in a vaccine-immunity versus hybrid-immunity population.

Precise editing of DNA methylation has emerged as a promising tool in disease biology but most applications are limited to in vitro systems. Here, we develop two transgenic mouse lines harboring an inducible dCas9-DNMT3A or dCas9-TET1 editor to enable tissue-specific DNA methylation editing in vivo.

CD44 expressed by fibroblastic reticular cells in secondary lymphoid organs regulates trafficking of dendritic cells, and thus has an essential role in the priming of T cells and the adaptive immune response.

Gene drives are genetic modifications designed to propagate efficiently through a population. Here, the authors develop a viral gene drive against herpes simplex virus 1 (HSV-1) and show that it propagates efficiently during HSV-1 infection in mice.

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a highly enriched cell surface antigen expressed in prostate cancer. Here the authors describe the design of STEAP1 directed CART cells and show their antitumor activity in preclinical models of prostate cancer, also in combination with a collagen binding domain-IL-12 fusion cytokine.

CAR-T cells are engineered to express CBD-IL-12 upon STEAP1 recognition to enhance tumour-specific immune responses in mice.

Gold nanoparticles that passively deliver CRISPR machinery to blood repopulating cells have been developed and are shown to be capable of precise editing of multiple genetic loci of therapeutic interest without cytotoxicity or reduced fitness.

Here the authors use a genome-wide approach to identify genetic variants associated with RNA isoform variation, uncovering new links between transcriptional regulation and complex traits. The findings can advance understanding of disease mechanisms.

Genome-wide CRISPRi screens for modulators of androgen receptor (AR) protein levels using live-cell quantitative endogenous AR fluorescence reporters identify PTGES3 as a new regulator of AR stability and function in prostate cancer.

Current methods for haematopoietic stem cell gene therapy are laborious and require special licensed facilities. Here the authors develop a semi-automated protocol using a commercially available device to allow for benchtop generation of gene-modified blood cell products for transplantation, that meet current standards.

The previous efforts to reprogramme tumour-associated macrophages (TAMs) to M1 phenotype have caused undesired side-effects. Here, the authors report targeted nanocarriers for delivering mRNA encoding M1-polarizing transcription factors to TAMs and show their efficacy in multiple mouse tumour models.

Carlson et al. show that DTCs within the PVN are protected from chemotherapy; targeting interactions between DTCs and the PVN enhances chemosensitivity and prevents bone metastasis.

The main challenge for anti-HSV therapy is to target latent virus in ganglionic neurons. Here, the authors report a well-tolerated anti-HSV gene editing approach against HSV which targets latent HSV genomes and leads to reductions of ganglionic viral loads, and viral shedding upon reactivation in mouse models.

Colleen Delaney and colleagues have developed a new culture system for umbilical cord blood progenitors that improves myeloid engraftment in cord blood transplants using a Notch ligand–mediated ex vivo expansion strategy. The study demonstrates rapid hematopoietic engraftment in a NOD/SCID mouse model and a phase 1 myeloablative cord blood transplantation trial. The strategy could lead to better clinical outcomes as a result of reduced morbidity and mortality.

Relapsed and/or refractory acute myeloid leukemia (AML) postallogeneic hematopoietic cell transplantation has limited treatment options. Here the authors report the clinical results and immune correlates of a phase I/II trial of adoptively transferred virus-specific donor CD8 + T cells engineered to express a WT1-specific T cell receptor in patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation.

Gene therapy is a rapidly growing field, but is hindered by efficacy and safety concerns, including those related to delivery methods. Here, inspired by the use of foam in the delivery of pharmaceuticals, Dr. Stephan and colleagues formulated foam as a safe and effective delivery platform for gene therapy.

Lower respiratory tract disease is a common complication after allogeneic hematopoietic cell transplant (HCT), but underlying reasons remain unclear. Here the authors show that HHV-6B detection in the lungs of allogeneic HCT recipients is associated with increased risk for death and distinct host gene expression profiles, implicating HHV-6B as a pulmonary pathogen in these patients.

The authors describe the isolation and characterization of broadly cross-neutralizing monoclonal antibodies (mAbs) against diverse H5Nx viruses from individuals who received a monovalent H5N1 vaccine 15 years ago. They identify five mAbs that potently neutralized the majority of H5 clades and protected against lethal 2.3.4.4b H5N1 infection in mice.

Expansion of human hematopoietic stem cells present in cord blood or bone marrow can be achieved by cell culture in a hydrogel, potentially facilitating clinical applications of hematopoietic cell transplantation.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

Simon, Bugos and colleagues report the design and characterization of monospecific and bispecific synthetic chimeric T cell receptors, conferring increased antigen sensitivity and antitumor activity in B cell malignancies and multiple myeloma models.

Complementary single-cell approaches show that a population of regulatory T cells co-expressing ICOS and IL-1 receptor type 1 is highly enriched in tumours but not in site-matched inflamed non-malignant tissue.

A study reveals that Fusobacterium nucleatum subspecies animalis is bifurcated into two distinct clades, and shows that only one of these dominates the colorectal cancer niche, probably through increased colonization of the human gastrointestinal tract.

Quiescent populations are a likely key source of treatment resistance in glioblastoma. Here, the authors characterize KAT5 as a critical mediator of quiescence and adoption of progenitor-like states.

Tropomyosin receptor kinase B (TrkB), encoded by the neurotrophic tyrosine receptor kinase 2 (NTRK2) gene, exhibits intricate splicing patterns and post-translational modifications. Here, the authors perform whole gene and transcript-level analyses and report the TrkB.T1 splice variant enhances PDGF-driven gliomas in vivo and augments PI3K signaling cascades in vitro.

Ex vivo engineering of antigen-specific T cells has shown therapeutic efficacy but can be costly and scarce. Here the authors show that in vitro-transcribed antigen receptor mRNA packaged in nanocarriers can directly induce, in vivo, transient their expression in circulating T cells to provide therapeutic effects in mouse models of cancer or viral infection.