Quan Liu

Photothermal therapy (PTT) leverages light-absorbing nanoparticles (NPs) to convert light energy into localized heat, providing a targeted and minimally invasive approach for tumor ablation. Despite its promise, PTT faces several limitations, chiefly the poor tissue penetration depth and the risk of cancer recurrence due to incomplete tumor eradication. Recent breakthroughs, however, reveal that carefully engineered NPs can trigger immunogenic cell death (ICD) within an optimal thermal range. This process releases a cascade of damageassociated molecular patterns (DAMPs), activating dendritic cells (DCs) and priming tumor-specific T-cell immunity. By converting immunologically “cold” tumors into “hot” ones, this strategy opens the door for synergistic combination therapies with immunotherapy. This review outlines cutting-edge progress across precious-metal, organic, and hybrid photothermal nanomaterials, emphasizing how PTT-triggered ICD works at the molecular level and highlighting key strategies to enhance synergy with other treatments, such as immunotherapy, radiotherapy (RT), and chemotherapy. It also explores future directions and the challenges that remain in improving ICD efficiency, overcoming immunosuppressive tumor microenvironments (TME), and translating these strategies into clinical practice.

Breast cancer is the most prevalent malignant tumor among women worldwide. Its progression is driven, in part, by mitochondrial metabolic dysregulation, which can also contribute to therapeutic resistance. Although targeting mitochondrial metabolism offers new opportunities for treatment, significant therapeutic challenges remain. These include metabolic heterogeneity among subtypes and individual patients, drug resistance arising from metabolic plasticity, and suboptimal clinical translation of metabolic therapies. This review systematically synthesizes the mitochondrial metabolic mechanisms underlying different breast cancer subtypes, emphasizing the spatial network regulatory functions of mitochondrial metabolism. It further critically evaluates combined therapeutic strategies targeting metabolic vulnerabilities. By integrating current research limitations with emerging breakthroughs, we outline novel therapeutic frameworks to advance the development of precision medicine approaches focused on mitochondrial metabolism.

Background: Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC). Methods: Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels. Results: Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1. Conclusions: AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments.

Objectives: Among the large number of members in the aldo-keto reductase families, aldo-keto reductase family one member C3 (AKR1C3) has been identified as a key player in hepatocellular carcinoma (HCC) progression, yet the specific regulatory mechanisms are still being unraveled. We aimed to validate the effects of AKR1C3 on cholesterol and bile acid (BA) metabolism both in vivo and in vitro , and to investigate its novel mechanisms in HCC progression. Methods: The differential expression of AKR1C3 in HCC and normal liver tissues was assessed using a public database and validated through cell experiments. The effects of AKR1C3 on liver cancer cell proliferation, migration, and invasion were verified using a cell counting kit-8 (CCK-8) assay, a plate clone formation experiment, and Transwell assays. The specific mechanism was predicted by RNA sequencing, and pathway proteins were validated by western blotting. Subcutaneous tumor formation experiments were used to confirm the effect of AKR1C3 on liver cancer proliferation in nude mice. Furthermore, the effect of AKR1C3 on lung metastasis was evaluated through the pulmonary metastasis model. Results: AKR1C3 is overexpressed in liver cancer and is positively correlated with poor prognosis. HCC cells showed a marked reduction in both proliferative activity and metastatic potential (migration and invasion) after AKR1C3 knockdown. RNA sequencing suggested that AKR1C3 was involved in cholesterol and BA metabolism. Western blotting showed that AKR1C3 promoted the expression of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase (HMGCR) and cholesterol 7α-hydroxylase (CYP7A1). Subsequently, knocking down AKR1C3 decreased cholesterol and BA levels. In vivo experiments confirmed that AKR1C3 knockdown inhibits tumor growth, suppresses lung metastasis, and lowers cholesterol and BA levels. Conclusions: AKR1C3 promotes cholesterol and BA synthesis through the HMGCR–CYP7A1 axes, thus accelerating liver cancer pathogenesis.

Breast cancer (BC) is the second leading cause of death among women worldwide. Immunotherapy has become an effective treatment for BC patients due to the rapid development of medical technology. Considerable breakthroughs have been made in research, marking the beginning of a new era in cancer treatment. Among them, various cancer immunotherapies such as immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer are effective and have good prospects. The tumor microenvironment (TME) plays a crucial role in determining the outcomes of tumor immunotherapy. Tumor-associated macrophages (TAMs) are a key component of the TME, with an immunomodulatory effect closely related to the immune evasion of tumor cells, thereby affecting malignant progression. TAMs also significantly affect the therapeutic effect of ICIs (such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors). TAMs are composed of multiple heterogeneous subpopulations, including M1 phenotypes macrophages (M1) and M2 phenotypes macrophages (M2). Furthermore, they mainly play an M2-like role and moderate a variety of harmful consequences such as angiogenesis, immunosuppression, and metastasis. Therefore, TAMs have become a key area of focus in the development of tumor therapies. However, several tumor immunotherapy studies demonstrated that ICIs are effective only in a small number of solid cancers, and tumor immunotherapy still faces relevant challenges in the treatment of solid tumors. This review explores the role of TAMs in BC immunotherapy, summarizing their involvement in BC development. It also explains the classification and functions of TAMs, outlines current tumor immunotherapy approaches and combination therapies, and discusses the challenges and potential strategies for TAMs in immuno-oncology treatments.

Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor-acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O₂^-•) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.

Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application. Graphical Abstract

Despite recent technological advancements in cell tumor DNA (ctDNA) mutation detection, challenges persist in identifying low-frequency mutations due to inadequate sensitivity and coverage of current procedures. Herein, we introduce a super-sensitivity and specificity technique for detecting ctDNA mutations, named HiCASE. The method utilizes PCR-based CRISPR, coupled with the restriction enzyme. In this work, HiCASE focuses on testing a series of EGFR mutations to provide enhanced detection technology for non–small cell lung cancer (NSCLC), enabling a detection sensitivity of 0.01% with 40 ng cell free DNA standard. When applied to a panel of 140 plasma samples from 120 NSCLC patients, HiCASE exhibits 88.1% clinical sensitivity and 100% specificity with 40 μL of plasma, higher than ddPCR and Super-ARMS assay. In addition, HiCASE can also clearly distinguish T790M/C797S mutations in different positions at a 1% variant allele frequency, offering valuable guidance for drug utilization. Indeed, the established HiCASE assay shows potential for clinical applications.

Mpox is an infectious viral disease, and, as of January 12, 2023, about 84 560 distinct cases have been detected, involving about 110 countries since May 2022. Most clustered regularly interspaced short palindromic repeat (CRISPR)-based detection methods require long assay time because of the pre-amplification to target nucleic acids. Herein, we designed a new prototypal mpox biosensor that allows amplification-free nucleic acid detection by combining CRISPR/Cas12b system and ultrasensitive graphene field-effect transistor (gFET). The CRISPR/Cas12b–gFET enabled the detection of the mpox virus (MPXV) DNA targets at a sensitivity of ∼1 aM within about 20 min. We designed several sgRNAs to recognize the target genes of MPXV and then Cas12b protein cleaved the target genes to form a double-strand break. The specificity of sgRNAs of MPXV designed was verified among other homologous Orthopoxviruses, and the sgRNA could distinguish between recent 2022 MPXV and West African MPXV with the mutation site, showing its potential application in MPXV detection. Thus, the demonstrated CRISPR–gFET detection technology could serve as a sensitive and rapid diagnostic tool for MPXV and other DNA viruses in the future.

Cancer is the second leading cause of death in the world and seriously affects the quality of life of patients. The diagnostic techniques for tumors mainly include tumor biomarker detection, instrumental examination, and tissue biopsy. In recent years, liquid technology represented by circulating tumor DNA (ctDNA) has gradually replaced traditional technology with its advantages of being non-invasive and accurate, its high specificity, and its high sensitivity. ctDNA may carry throughout the circulatory system through tumor cell necrosis, apoptosis, circulating exosome secretion, etc., carrying the characteristic changes in tumors, such as mutation, methylation, microsatellite instability, gene rearrangement, etc. In this paper, ctDNA mutation and methylation, as the objects to describe the preparation process before ctDNA analysis, and the detection methods of two gene-level changes, including a series of enrichment detection techniques derived from PCR, sequencing-based detection techniques, and comprehensive detection techniques, are combined with new materials. In addition, the role of ctDNA in various stages of cancer development is summarized, such as early screening, diagnosis, molecular typing, prognosis prediction, recurrence monitoring, and drug guidance. In summary, ctDNA is an ideal biomarker involved in the whole process of tumor development.