Clinical approaches for cancer therapy face several interrelated challenges involving inefficient drug delivery, potential adverse side effects, and inconvenience. Here, we present an integrated wearable flexible ultrasound microneedle patch (wf-UMP) that serves as a portable platform for convenient, efficient, and minimally invasive cancer therapy. The wf-UMP adopts an all-in-one bioelectronic concept, which integrates a stretchable lead-free ultrasound transducer array for acoustic emission, a bioadhesive hydrogel elastomer for robust adhesion and acoustic coupling, and a dissolvable microneedle patch loaded with biocompatible piezoelectric nanoparticles for painless drug delivery and reactive oxygen species generation. With soft mechanical properties and enhanced electromechanical performance, wf-UMP can be robustly worn on curved and dynamic tissue surfaces for easy and effective manipulation. In preclinical studies involving mice, wf-UMP demonstrated notable anticancer effects by inducing tumor cell apoptosis, amplifying oxidative stress, and modulating immune cell proliferation. Furthermore, the synergistic immunotherapy induced by wf-UMP and Anti-PD1 further improved anticancer immunity by activating immunogenic cell death and regulating macrophages polarization, inhibiting distant tumor growth and tumor recurrence.
© 2025. The Author(s).

Glioma, particularly glioblastoma (GBM), is a highly aggressive tumor with limited responsiveness to immunotherapy. PANoptosis, a form of programmed cell death merging pyroptosis, apoptosis, and necroptosis, plays an important role in reshaping the tumor microenvironment (TME) and enhancing immunotherapy effectiveness. This study investigates PANoptosis dynamics in glioma and explores the therapeutic potential of its activation, particularly through natural compounds such as cinobufagin.
We comprehensively analyzed PANoptosis-related genes (PANoRGs) in multiple glioma cohorts, identifying different PANoptosis patterns and constructing the PANoptosis enrichment score (PANoScore) to evaluate its relationship with patient prognosis and immune activity. Cinobufagin, identified as a PANoptosis activator, was evaluated for its ability to induce PANoptosis and enhance anti-tumor immune responses both in vitro and in vivo GBM models.
Our findings indicate that high PANoScore gliomas showed increased immune cell infiltration, particularly effector T cells, and enhanced sensitivity to immunotherapies. Cinobufagin effectively induced PANoptosis, leading to increased immunogenic cell death, facilitated tumor-associated microglia/macrophages (TAMs) polarization towards an M1-like phenotype while augmenting CD4+/CD8 + T cell infiltration and activation. Importantly, cinobufagin combined with anti-PD-1 therapy exhibited significant synergistic effects and prolonged survival in GBM models.
These findings highlight the therapeutic potential of PANoptosis-targeting agents, such as cinobufagin, in combination with immunotherapy, offering a promising approach to convert "cold" tumors into "hot" ones and improving glioma treatment outcomes.
© 2025. The Author(s).

Individuals with a loss-of-function single-nucleotide polymorphism in the gene encoding PTPN22 have an increased risk for autoimmune diseases, and patients with cancer with such alleles may respond better to checkpoint blockade immunotherapy. Studies in PTPN22 knockout (KO) mice have established it as a negative regulator of T cell responses in cancer models. However, the role of PTPN22 in distinct immune cell compartments, such as dendritic cells (DCs), remains undefined.
We developed a novel PTPN22 conditional KO (cKO) mouse model that enables specific deletion in CD11c+ DCs by crossing to CD11c-Cre transgenic mice. Antitumor immunity was characterized using the B16.SIY and MC38.SIY cancer models and immune profiles of relevant tissues were evaluated by spectral flow cytometry. Antigen uptake, processing, and presentation, as well as DC proliferation to Flt3L, were characterized ex vivo.
Deletion of PTPN22 in DCs resulted in augmented antitumor immunity in multiple syngeneic tumor models. Tumor antigen-specific CD8+ T cells were increased in the tumor microenvironment (TME) of PTPN22 cKO mice and improved tumor control was CD8+ T cell-dependent. Augmented T cell priming was also detected at early time points in the draining lymph nodes, and these effects were correlated with an increased number of proliferating CD103+ DCs, also seen in the TME. In vitro studies revealed increased DC proliferation in response to Flt3L, as well as increased antigen processing and presentation. PTPN22 cKO mice bearing MC38 parental tumors showed combinatorial benefit with anti-PD-L1 therapy.
Deletion of PTPN22 in DCs is sufficient to drive an augmented tumor antigen-specific T cell response, resulting in enhanced tumor control. PTPN22 negatively regulates DC proliferation and antigen processing and presentation. Our work argues that PTPN22 is an attractive therapeutic target for cancer immunotherapy and highlights the potential to modulate antitumor immunity through the manipulation of DC signaling.
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.
© 2023. Springer Nature Limited.

SOX10 is a key regulator of melanoma progression and promotes a melanocytic/differentiated state. Here we identified melanoma cell lines lacking SOX10 expression which retain their in vivo growth capabilities. More importantly, we find that SOX10 can regulate T-cell infiltration in melanoma while also decreasing common cancer stem cell (CSC) properties. We show that SOX10 regulates CEACAM1, a surface protein with immunomodulatory properties. SOX10 directly binds to a distal CEACAM1 promoter region approximately 3-4kbps from the CEACAM1 transcriptional start site. Furthermore, we show that a SOX10-CEACAM1 axis can suppress CD8+ T-cell infiltration as well as reduce CSC pool within tumors, leading to reduced tumor growth. Overall, these results identify SOX10 as a direct regulator of CEACAM1, and uncover both a pro- and anti-tumorigenic roles for SOX10 in melanoma.
Crown Copyright © 2022.