Immune checkpoint blockade (ICB) therapies for solid tumors often fail due to resistance, necessitating new strategies. While efforts target IFNγ signaling or antigen presentation, other immune evasion mechanisms are unclear. Here, we identify Monoacylglycerol O-Acyltransferase 1 (Mogat1) as a critical modulator of tumor immune evasion using an in vivo transcriptomic screen in progressing tumors. We find that tumors exploit Mogat1 to sequester fatty acids into triglycerides, a metabolic adaptation that fuels growth and fosters an immunosuppressive microenvironment, enabling immune escape. Genetic inhibition of Mogat1 suppresses tumor growth by promoting T-cell infiltration and enhancing their tumor-killing ability. Importantly, Mogat1 loss sensitizes tumors to PD-1 blockade, overcoming resistance and suggesting reduced reliance on conventional antigen presentation. Our findings reveal a lipid metabolism-centered immune evasion mechanism and highlight Mogat1 as a potential target to improve cancer immunotherapy.
© 2025. The Author(s).

Diverse T cell types accumulate at the human maternal fetal interface (MFI) during pregnancy to orchestrate immune tolerance for foreign fetal/placental tissues and immunity to pathogens. Yet, the dynamics of T cell influx and function at the MFI remain poorly defined. Conventional specific pathogen free (SPF) murine models fail to replicate the number and diversity of T cells in the human MFI, hindering mechanistic study of MFI T cells. Here we present an innovative use of a natural microbial exposure (NME) mouse model that enhances T cell influx and diversity in the MFI. We defined changes in the MFI of NME mice, relative to SPF mice and human tissues using transcriptomic and proteomic approaches. Physiological maternal microbial burden reproduced key features of human MFI immunology by i) significantly increasing the numbers and diversity of CD4 and CD8 effector and memory T cells at the MFI; ii) skewing the CD8 T cell composition towards tissue resident memory phenotypes with increased signatures of activation and dysfunction similar to human decidual T cells; and iii) expanding unconventional γδ T cells and Killer Lectin-like Receptors (KLR) expressing T cell types at the MFI, representative of an enhanced ability to interact with placental trophoblasts or infected cells. Thus, maternal microbial exposure induces vast changes to T cell numbers, diversity and functions at the MFI that models human MFI T cells with great fidelity. The NME model allows for improved translational investigation of the mechanisms of T cell tolerance, immunity, and inflammation in pregnancy.
Copyright © 2025 Whillock, Smith, Burger, Sridhar, Lindgren, Berg, Tsuda, Mahajan, Tilburgs and Schuldt.

Diabetic retinopathy features damage to the retinal microvasculature that causes vessels to leak and proliferate and can lead to vision loss and blindness. Inflammation contributes to the development of diabetic retinopathy, but little is known about the role of the adaptive immune system, including the benefits of augmenting the Forkhead box protein P3 (Foxp3) regulatory T cell (Treg) compartment. We aimed to determine whether treatment with low-dose IL-2 expands and activates Tregs and reduces CD8+ T cells in the retina, and attenuates retinal inflammation and vasculopathy in murine models of diabetic retinopathy and neovascular retinopathy.
Mouse models of streptozocin-induced diabetes and oxygen-induced retinopathy (OIR) were administered low-dose IL-2 (25,000 U) or vehicle (sterile water) by i.p. injection. Reporter mice expressing Foxp3 as a red fluorescent protein (RFP) conjugate or CD8 as a green fluorescent protein (GFP) conjugate were used to evaluate Foxp3+ Tregs and CD8+ T cells, respectively, in blood, lymphoid organs and retina using flow cytometry or confocal microscopy. Vasculopathy and the expression of angiogenic and inflammatory factors were assessed in the retina.
Low-dose IL-2 significantly expanded CD4+CD25+Foxp3+ Tregs in the blood and spleen of mouse models of OIR and diabetes (1.4- to 1.9-fold increase, p<0.01). This expansion enhanced Treg functionality, increasing the expression of cytotoxic T-lymphocyte-associated protein4 (CTLA4), programmed cell death protein1 (PD1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), and increased the ratio of Tregs to CD8+ T cells. This was accompanied in the retina by a twofold increase in Foxp3+ Tregs (diabetes: 3.01 ± 0.41 vs 5.90 ± 1.25 cells per field, p<0.001; OIR: 4.41 ± 1.48 vs 10.05 ± 2.91 cells per field, p<0.001) and a reduction in CD8+ T cells (diabetes: 4.65 ± 0.58 vs 3.00 ± 0.81 cells per field, p<0.01; OIR: 5.51 ± 1.33 vs 3.17 ± 1.14 cells per field, p<0.01). Low-dose IL-2 reduced the levels of the potent inflammatory factors intercellular adhesion protein1 and TNF and the chemokine IFNγ-inducible protein10 (IP-10) in the retina. Importantly, low-dose IL-2 treatment effectively attenuated retinal vasculopathy, with marked reductions in acellular capillaries (diabetes: 0.48-fold decrease, p<0.001), neovascularisation (OIR: 0.68-fold decrease, p<0.01) and vascular leakage, and expression of vascular endothelial growth factor.
This study highlights the therapeutic potential of low-dose IL-2 to reduce retinal inflammation and severe vascular injury by boosting Tregs and reducing CD8+ T cells and inflammatory factors.
© 2025. The Author(s).

Esophageal squamous cell carcinoma (ESCC) is a common and aggressive cancer with limited responses to immunotherapy. High mobility group A1 (HMGA1), a chromatin remodeling protein, plays a key role in tumor progression, but its impact on anti-tumor immunity in ESCC remains unclear. Here we show that HMGA1 suppresses the stimulator of interferon genes (STING), inhibiting type I interferon secretion, downregulating interferon-stimulated genes, and impairing tumor-infiltrating lymphocyte (TIL) recruitment. HMGA1 inhibits STING transcription by competing with the coactivator CBP/p300 for binding to CREB. ESCCs from genetically modified mouse models with altered HMGA1 and STING expression exhibit varying TIL levels and sensitivity to STING agonists. Additionally, we design and synthesize a series of HMGA1 inhibitors, including a perylene-based nanoparticle, PDIC-DPC, which effectively inhibits HMGA1 and enhances TIL infiltration. Our findings identify HMGA1 as a critical immune checkpoint in ESCC and suggest that targeting HMGA1 could improve immunotherapy outcomes.
© 2025. The Author(s).

Antigenic peptide-based mRNA vaccines have been explored for immunotherapeutic use in various types of cancer because of their advantages in activating durable and specific immune responses. However, their role in modulating tumor metastasis is still unclear. Here, we identify a conserved linear epitope-based peptide, Ma3P, located in the proteolytic region of major histocompatibility complex (MHC) class I-related chain A (MICA) α3 and further design mCM10-L, an mRNA vaccine that encodes the carrier protein CRM197 and 10 tandem repeats of Ma3P. We demonstrate that vaccination with mCM10-L induces the production of specific antibodies that block MICA/B α1/2 shedding, activate CD8+ T cells and natural killer (NK) cells, and significantly inhibit MICA/B+ tumor metastasis in mice. Furthermore, mCM10-L stimulation triggers the production of specific antibodies to promote MICA/B-mediated immune killing in an in-vitro-interacting human organoid model and humanized mice. Our results indicate the potential clinical application prospects of the mCM10-L vaccine.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.