ACIR

Altenburger et al. showed that although in vitro-activated CD8+ T cells that were attached to DCs for long periods exhibited persistent TCR signaling during cell division, in lymphoid tissue, DCs and T cells detached before T cell proliferation began. DC-attached T cells were transiently unresponsive, but regained CCR7 response to CCL19/21 over 24-48hrs to reposition F-actin-promoting factor DOCK2 away from the immune synapse and allow T cell detachment, effector gene transcription, and enhanced cytolysis. Prolonged DC–T cell interaction increased PD-1 and LAG3. Detachment favored increased effector function that lasted throughout the memory phase. bit.ly/49w2KyF

Wei et al. used Foxp3-transduced conventional T cells as a gain-of-function probe, and identified an endogenous Foxp3+ subset that acquired Treg-like transcriptional, chromatin, and suppressive features, exclusively in vivo. Endogenous Foxp3 induction in vivo required a permissive environment created by reduced AKT-mTOR signaling and Foxp3 engagement with STAT5 and NF-κB at Foxp3 regulatory elements. Foxp3 drove a stepwise chromatin remodeling program at Foxp3-induced open chromatin regions, establishing NFκB-linked core modules shared across Treg subsets, and effector-specific modules co-regulated with AP-1. bit.ly/4dniipA

Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment. bit.ly/4dh2TbP  @harvardmed

Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival. bit.ly/3R45xc9

Tselikas and Susini et al. evaluated whether intratumoral anti-CTLA-4 was safe and could reduce severe AEs in the phase 1b NIVIPIT trail bit.ly/4tCeEyn @GustaveRoussy @LambrosTselikas Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

Among a retrospective cohort of 84 HCC patients treated with ICB, those who received their first ICB dose in the morning (prior to 12 noon) had increased PFS (and a trend in OS) compared to those receiving a first dose in the afternoon. The timing of subsequent doses did not have a similar stratifying effect, and morning dosing did not raise the rate of irAEs. Comparing baseline and early on-treatment blood samples, Li et al. found that patients first receiving ICB in the morning had diminished induction of certain cytokines (IL-6, IL-1B, VEGF-A, and IL-21) and a greater expansion of cytotoxic CD8+ Tcm cells, compared to those receiving an afternoon dose. bit.ly/4tRBAKL  @HopkinsMedicine

Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology. bit.ly/4extaDK

Our team will be attending CIMT in Mainz, Germany on May 11-13. Stop by our booth to chat and share what you're working on 👀 #CIMT2026

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice. bit.ly/4nhFmL5

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy. bit.ly/4wfjBQ7  @CornellRsrch

As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling. bit.ly/4wlNkaf

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth. bit.ly/4tq8dhH @EmoryUniversity @danaFarber @rafiahmed_lab

In tumors that have lost expression of MHC-I, Treg ablation could unleash NK cell cytotoxicity and help to control CD8+ T cell-resistant tumors bit.ly/4uBrRII 👉 Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects. @berkeleyMCB @david_raulet

Lin et al. engineered a spleen-targeted neoantigen mRNA vaccine (STNvac) using a two-component LNP formulation that selectively delivered mRNA to splenic DCs and prompted robust neoantigen-specific CD8+ T cell response in an orthotopic Hepa1-6 HCC model. STNvac induced a distinct ISG15+ CD8+ T cell subset with enhanced cytotoxicity that mediated antigen-specific tumor clearance. Single-cell and spatial analyses showed interaction between ISG15+ CD8+ T cells and intratumoral APCs via a GZMA–F2R axis, which drove ISG15+ CD8+ T cell activation, proliferation, and organization into TLSs in human and mouse HCC specimens. bit.ly/48vgIAz

Han, Zhou, and Dwivedy et al. developed cationic α-helical polypeptides that can condense and stabilize encoding mRNA in nanosized polyplexes. Upon s.c. administration, these polyplexes are taken up by DCs in lymph nodes, induce activation by NF-κB, IRF, p-STING, and cGAS, and improve the processing and presentation of mRNA-encoded antigens compared to mRNA-LNP, lipoplexes, or free mRNA. In E.G7-OVA lymphoma and 4T1 TNBC models, polyplexes elicited potent neoantigen-specific CD8+ T cells, reprogrammed the TIME (enriching DCs, CD86+ macrophages, and CD8+ T cells), enhanced therapeutic efficacy, and synergized with anti-PD-1. bit.ly/4tGkBLk  @AbhisekDwivedy

🧬 Big news in vaccine science: Researchers at Mount Sinai just flipped a core assumption about how mRNA vaccines work. It turns out immune cells don't need to directly express the vaccine — muscle cells boost immunity, while liver cells actually suppress it. By engineering mRNA vaccines to skip liver cells, scientists saw tumor burden drop by 50%+ in lymphoma models. This could reshape how we design cancer vaccines, COVID boosters, and gene therapies alike. 📄 Published in Nature Biotechnology (April 29, 2026) bit.ly/4tNZqr2

Kishida et al. showed that immune-induced TCR-like antibodies (iTabs) – antibodies that are specific to an antigen peptide–MHC-II complex – were produced during helper T cell responses to immunization with various antigens. These iTabs induced antigen-dependent depletion of target cells, blocked TCR recognition of specific peptide–MHC-II complexes, and prevented activation of antigen-specific T cells, but only when the presented peptides contained specific flanking residues. In a mouse model, treatment with iTabs or immunization with a peptide that induced iTabs effectively limited the development of autoimmune encephalomyelitis. bit.ly/4vTXDSt

Using single-cell and spatial transcriptomics in human and rat models, Bui et al. mapped immune remodeling of normal breast, pre-malignant (DCIS) , and invasive (IBC) breast cancer and identified a proliferative FOXP3int MKI67hi cycling Treg (cycTreg) subset. CycTregs emerged at the DCIS-IBC junction, expanded in IBC, and predicted CD8+ infiltration, TCR diversity, disease-specific survival, and DCIS recurrence. CycTreg abundance correlated with CLEC10A+ cDC2s, high HLA class II, and IL-33-producing CAFs. OX40 agonism plus anti-PD-L1 or IL-33 blockade reduced cycTreg, remodeled CAF states, and restored antitumor immunosurveillance. bit.ly/4tScmMc @dfci_breastOnc @danaFarber

Addressing the need for superior toxin delivery and safety for AML and MDS therapies, Marx et al. developed Debio 1562M, a next-generation ADC targeting CD37, which is broadly expressed on AML and MDS blasts. Debio 1562M (with a drug [DM1]-to-naratuximab ratio of 8, and a cathepsin-cleavable linker) was efficiently internalized and killed blast cells in blood and bone marrow. In multiple models, Debio 1562M outperformed standard-of-care treatments, and demonstrated broad and efficient anti-leukemic activity on all AML subtypes. Compared to 1st generation CD37 ADC, Debio 1562M had an improved toxicity profile in mice, and is in a phase 1 trial for r/r AML and high-risk MDS. bit.ly/4t3sUQc  @DebiopharmNews

Aiming to avoid allogeneic CAR-T rejection, Zhang and Li et al. found that a CD70 CAR depleted donor-mismatched, activated (CD70+) T and NK cells in coculture. Dual CD19/CD70 CAR T cells responded to CD19+ tumor cells comparably to single CD19 CAR-T, but also recognized CD70+ target cells and protected against allo-mediated killing. Dual CD19-CD70 CAR T cells transiently eliminated B cells in CD34-humanized mice, and depleted B cells and autoantibodies in lupus PBMC-humanized mice, with superior persistence of CD19 CAR-T cells, without lymphodepletion. CD70 CAR variants were optimized for expression and functionality. bit.ly/4cZvtNp  @AllogeneTx