Light-triggered toll-like receptor activation in a nanoscale metal-organic framework for synergistic PDT and cancer immunotherapy.

Although innate immune modulators (IIMs) have shown promise as cancer immunotherapeutics, their clinical application is hindered by the challenge of achieving tumour-specific activation while minimizing systemic immune-related toxicity. Nanoscale metal-organic frameworks (MOFs) have emerged as effective carriers for photosensitizers to enable photodynamic therapy (PDT), which induces immunogenic cell death reactive oxygen species (ROS) generation. We hypothesized that covalent conjugation of IMMs to nanoscale MOFs through ROS-cleavable linkers could localize immune activation to the tumour microenvironment while synergizing with PDT to enhance antitumour immunity.

NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.

Cancer-associated fibroblasts (CAFs) have a pivotal cancer-supportive role, yet CAF-targeted therapies are lacking. Here, using spatial transcriptomics and single-cell RNA sequencing, we investigate the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumour.

Nanoscale Donor-Acceptor Covalent Organic Frameworks for Mitochondria-Targeted Sonodynamic Therapy and Antitumor Immunity.

Sonodynamic therapy (SDT) based on O-dependent type II sonosensitizers (SSs) is limited by the hypoxic tumor microenvironment and aggregation-induced quenching (AIQ) of SSs. Type I SSs can generate reactive oxygen species (ROS) with reduced O dependence, but their efficacy is still constrained by the high electron-hole recombination rates and low ROS yields. Here, we report the synthesis of a novel two-dimensional nanoscale covalent organic framework (nCOF), Td-Pc, for mitochondria-targeted type I/II SDT.

The dark side of radiotherapy.

Radiotherapy (RT), while pivotal in cancer control, may paradoxically promote metastasis through systemic effects. Emerging evidence implicates RT-induced growth factors and immune modulation-especially via amphiregulin-epidermal growth factor receptor (EGFR) signaling-in facilitating metastatic outgrowth at distant sites. This effect underscores the need to refine RT strategies, identify high-risk patients, and explore therapeutic combinations targeting myeloid cells and EGFR pathways to mitigate pro-metastatic consequences and optimize outcomes in the immunotherapy era.

A universal chimeric antigen receptor (CAR)-fragment antibody binder (FAB) split system for cancer immunotherapy.

Chimeric antigen receptor (CAR) T cell therapy has shown extraordinary results in treating hematological cancer but faces challenges like antigen loss, toxicity, and complex manufacturing. Universal and modular CAR constructs offer improved flexibility, safety, and cost-effectiveness over conventional CAR constructs. We present a CAR-fragment antibody binder (Fab) platform on the basis of an engineered protein G variant (GA1) and Fab scaffolds.

Tumor aneuploidy as a prognostic and predictive biomarker in immune checkpoint blockade.

Aneuploidy, a hallmark of cancer characterized by chromosome imbalances, drives tumorigenesis and facilitates cancer immune evasion. While high tumor aneuploidy is linked to immune checkpoint blockade (ICB) resistance and poor prognosis, evidence suggests that this resistance can be overcome through treatment intensification, for example, with the addition of ablative radiotherapy to ICB. In this Perspective, we argue that the predictive value of aneuploidy complements established biomarkers, such as tumor mutational burden (TMB) or programmed death ligand 1 (PD-L1) expression.

Synthesis of DOTA-Based Sc Radiopharmaceuticals Using Cyclotron-Produced Sc as Exemplified by [Sc]Sc-PSMA-617 for PSMA PET Imaging.

The implementation of theranostics in oncologic nuclear medicine has exhibited immense potential in improving patient outcomes in prostate cancer with the implementation of [Ga]Ga-PSMA-11 PET and [Lu]Lu-PSMA-617 into clinical practice. However, the correlation between radiopharmaceutical biodistributions seen with [Ga]Ga-PSMA-11 PET imaging and downstream [Lu]Lu-PSMA-617 therapy remains imperfect. This suggests that prostate cancer theranostics could potentially be further refined through the implementation of true theranostics, tandem pairs of diagnostic and therapeutic radiopharmaceuticals that utilize the same ligand and element, thus yielding identical pharmacokinetics.

YTHDFs as radiotherapy checkpoints in tumor immunity.

Radiotherapy (RT), a cornerstone of cancer treatment, exerts its therapeutic effects primarily by inducing DNA damage in tumor cells and modulating the tumor immune microenvironment (TIME). Despite its efficacy, RT is often counteracted by tumor-intrinsic mechanisms, such as DNA damage repair, as well as immune-suppressive responses. YTHDF proteins, key N6-methyladenosine (m6A) readers, have emerged as pivotal regulators of tumor progression, DNA repair, and immune cell function, making them promising targets for enhancing RT efficacy.

Radiation-induced amphiregulin drives tumour metastasis.

The anti-tumour effect of radiotherapy beyond the treatment field-the abscopal effect-has garnered much interest. However, the potentially deleterious effect of radiation in promoting metastasis is less well studied. Here we show that radiotherapy induces the expression of the EGFR ligand amphiregulin in tumour cells, which reprogrammes EGFR-expressing myeloid cells toward an immunosuppressive phenotype and reduces phagocytosis.

Transforming malignant tumors into vulnerable phenotypes via nanoscale coordination polymer mediated cell senescence and photodynamic therapy.

Induction of senescence in cancer cells can thwart the proliferation of malignant tumors. Herein we report the design of AZT-P/pyro nanoscale coordination polymer particles consisting of 3-azido-2,3-dideoxythymidine monophosphate (AZT-P) in the core and photosensitizing pyro-lipid (pyro) in the shell for potent antitumor treatment. Gradual release of AZT-P in response to an acidic tumor microenvironment transforms cancer cells with unlimited proliferation capacity into senescent cells that are vulnerable to reactive oxygen species (ROS).

Facts and Hopes in Radioimmunotherapy of Oligometastatic Disease.

The oligometastatic state, characterized by limited metastatic dissemination, challenges the view that metastatic cancer is widespread and incurable. Evidence suggests that select patients with restricted metastases may achieve long-term disease control or even cure with local therapies, such as surgery or stereotactic body radiotherapy (SBRT). Radiotherapy induces complex, dose-dependent effects on the tumor microenvironment, including the release of immunogenic cytokines and damage-associated molecular patterns, enhanced antigen presentation on cancer cells, and infiltration of effector T cells, NK cells, and macrophages.

Designing live bacterial therapeutics for cancer.

Humans are home to a diverse community of bacteria, many of which form symbiotic relationships with their host. Notably, tumors can also harbor their own unique bacterial populations that can influence tumor growth and progression. These bacteria, which selectively colonize hypoxic and acidic tumor microenvironments, present a novel therapeutic strategy to combat cancer.

Proceedings of the National Cancer Institute Workshop on combining immunotherapy with radiotherapy: challenges and opportunities for clinical translation.

Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear.

Nanoparticle-Mediated Toll-Like Receptor Activation and Dual Immune Checkpoint Downregulation for Potent Cancer Immunotherapy.

Dual blockade of CD47 and PD-L1 immune checkpoints has shown potential in cancer treatment, but its clinical application is hindered by the on-target off-tumor immunotoxicities of monoclonal antibodies. Herein, we report a core-shell nanoparticle, PPA/HG, comprising polyinosinic: polycytidylic acid (PPA) in the core and a cholesterol-conjugated prodrug of 3-(hydroxyolinoyl)glycine (HG) on the shell, for potent cancer immunotherapy. PPA/HG shows a long half-life in the bloodstream to efficiently accumulate in tumors, where PPA/HG rapidly releases HG and PPA.

Metal-organic layer delivers 3-bromopyruvate to mitochondria for metabolic regulation and cancer radio-immunotherapy.

Abnormal cancer metabolism causes hypoxia and immunosuppression, limiting the anti-tumor efficacy of radiotherapy. Herein, we report a positively charged, mitochondria-targeted nanoscale metal-organic layer conjugated with 3-bromopyruvate (BP), BP/Hf-Ir, for metabolic reprogramming and radiosensitization. BP/Hf-Ir disrupts oxidative phosphorylation and glycolysis, reducing energy production and alleviating hypoxia to enhance radiotherapy and anti-tumor immunity.

Ionizing radiation improves skin bacterial dysbiosis in cutaneous T-cell lymphoma.

Introduction: Cutaneous T-cell lymphoma (CTCL) is closely associated with the host microbiome. While recent evidence suggests that shifts in specific bacterial taxa are associated with response to UV-B, a form of non-ionizing radiation, the impact of ionizing radiation (IR) has not been investigated.

Methods: 16S rRNA and gene amplicon sequencing were performed on DNA extracted from swabs of lesional/non-lesional skin of 12 CTCL patients before/after TSEBT or local IR and from 25 matched healthy controls (HC).

-methyladenosine reader YTHDF2 in cell state transition and antitumor immunity.

Recent studies have revealed that the YTHDF family proteins bind preferentially to the -methyladenosine (mA)-modified mRNA and regulate the functions of these RNAs in different cell types. YTHDF2, the first identified mA reader in mammals, has garnered significant attention because of its profound effect to regulate the mA epitranscriptome in multiple biological processes. Here, we review current knowledge on the mechanisms by which YTHDF2 exerts its functions and discuss recent advances that underscore the multifaceted role of YTHDF2 in development, stem cell expansion, and immune evasion.

Pushing the boundaries of radiotherapy-immunotherapy combinations: highlights from the 7 immunorad conference.

Over the last decade, the annual Immunorad Conference, held under the joint auspicies of Gustave Roussy (Villejuif, France) and the Weill Cornell Medical College (New-York, USA) has aimed at exploring the latest advancements in the fields of tumor immunology and radiotherapy-immunotherapy combinations for the treatment of cancer. Gathering medical oncologists, radiation oncologists, physicians and researchers with esteemed expertise in these fields, the Immunorad Conference bridges the gap between preclinical outcomes and clinical opportunities. Thus, it paves a promising way toward optimizing radiotherapy-immunotherapy combinations and, from a broader perspective, improving therapeutic strategies for patients with cancer.

Erratum: Ultrathin Metal-Organic-Layer Mediated Radiotherapy-Radiodynamic Therapy.

[This corrects the article PMC7442115.].

Nanoscale Mixed-Ligand Metal-Organic Framework for X-ray Stimulated Cancer Therapy.

Concurrent localized radiotherapy and systemic chemotherapy are standards of care for many cancers, but these treatment regimens cause severe adverse effects in many patients. Herein, we report the design of a mixed-ligand nanoscale metal-organic framework (nMOF) with the ability to simultaneously enhance radiotherapeutic effects and trigger the release of a potent chemotherapeutic under X-ray irradiation. We synthesized a new functional quaterphenyl dicarboxylate ligand conjugated with SN38 (HQP-SN) via a hydroxyl radical-responsive covalent linkage.

Two decades of advances in clinical oncology - lessons learned and future directions.

Since the publication of the first issue of , we have witnessed advances in multiple research areas that have culminated in improved outcomes for many cancer types, although substantial unmet needs remain for a majority of patients worldwide. Here, we have asked experts in several key specialities to reflect on the progress from the past 20 years and propose the next steps to enable further advances. Although we are aware that this Viewpoint cannot provide full coverage of the vast field that is clinical oncology, we hope that these messages inspire a diverse range of readers.

Digitonin-Loaded Nanoscale Metal-Organic Framework for Mitochondria-Targeted Radiotherapy-Radiodynamic Therapy and Disulfidptosis.

The efficacy of radiotherapy (RT) is limited by inefficient X-ray absorption and reactive oxygen species generation, upregulation of immunosuppressive factors, and a reducing tumor microenvironment (TME). Here, the design of a mitochondria-targeted and digitonin (Dig)-loaded nanoscale metal-organic framework, Th-Ir-DBB/Dig, is reported to overcome these limitations and elicit strong antitumor effects upon low-dose X-ray irradiation. Built from ThO(OH) secondary building units (SBUs) and photosensitizing Ir(DBB)(ppy) (Ir-DBB, DBB = 4,4'-di(4-benzoato)-2,2'-bipyridine; ppy = 2-phenylpyridine) ligands, Th-Ir-DBB exhibits strong RT-radiodynamic therapy (RDT) effects via potent radiosensitization with high-Z SBUs for hydroxyl radical generation and efficient excitation of Ir-DBB ligands for singlet oxygen production.