Neoadjuvant immunotherapy has shown promising short-term outcomes of perioperative treatments for resectable non-small cell lung cancer (NSCLC) and is expected to release long-term survival benefits. Here, we reported the long-term prognostic value of 18F-FDG PET/CT over ∼a 5-year follow-up.

Polydopamine (PDA) possesses potential as a photothermal agent for tumor treatment owing to its photothermal capacity, chemical modifiability, excellent biocompatibility, and selective biodegradability. However, weak near-infrared (NIR) light absorption seriously hinders its actual utilization, especially in NIR-II. This study presents a novel molecularly modified PDA with remarkably increased NIR absorption and remarkably enhanced photothermal conversion capacity in both NIR-I and NIR-II. Dopamine monomers are covalently bound with elaborately selected 2,6-pyridinedicarboxylic acid (DPA) through an amidation reaction and then undergo an oxidative polymerization to form DPA-doped PDA nanoparticles (DPA-PDA NPs). By constructing donor-acceptor pairs and extending the conjugation length of molecular units, the energy band gap of DPA-PDA between the highest occupied molecular orbital and the lowest unoccupied molecular orbital is diminished from 0.77 to 0.45 eV, facilitating the electron low-energy transition. Meanwhile, the content of carbon-centered free radicals is obviously raised via suppressing their dimerization and quenching by the conjugation effect and steric hindrance effect, where the strengthened electron spin and vibration may promote charge and energy transfers, increasing and accelerating the excited electron nonradiative decay. As a result, the DPA-PDA NPs exhibit the enhanced NIR light absorption (196 and 205% over PDA) and much higher photothermal conversion efficiency (1.4 and 2.1 times that of PDA) under 808 and 1064 nm irradiation, respectively, achieving more effective tumor cells inhibition in vitro and tumor ablation in vivo. Interestingly, photothermal therapies with DPA-PDA for tumor-bearing mice emerge with higher tumor elimination (nearly 100%) under 1064 nm irradiation than that under 808 nm irradiation (94.3%), without recurrence within 20 days, which is attributed to both the enhanced photothermal capacity of DPA-PDA and the stronger tissue penetration ability of NIR-II. This design provides a new option to enhance the photothermal capacity of polydopamine as an applicative photothermal agent for tumor therapy.

Endocrine therapy is an essential treatment to improve disease-free and overall survival in patients with hormone receptor-positive breast cancer. However, symptoms associated with endocrine therapy severely affect patients' quality of life and medication adherence. To inform symptom management strategies, this study systematically reviews research on patients' symptom experiences and coping strategies during endocrine therapy.

Although the programmed cell death protein 1 (PD-1) blockade has been authorized for the treatment of recurrent and metastatic cervical cancer (CC) patients, a significant proportion of CC patients show low objective response rates (ORR) to immune checkpoint blockades (ICBs). Therefore, identifying novel combination treatment strategies to enhance ICBs therapeutic efficacy for CC patients is urgently needed. Here, we discovered that CD39 was highly expressed in exhausted CD8 + T cells from 10 CC patients in our center via single-cell RNA sequencing (scRNA-seq). Furthermore, we validated that CC patients with CD39 highly expressed in CD8 + T cells associated with poor prognosis and immunoevasive subtype of CC both in cohort from our center and the Cancer Genome Atlas (TCGA) database. Moreover, it was also confirmed that CD39-inhibiting not only enhanced the cytotoxicity of CD8 + tumor-infiltrating lymphocytes (TILs) but also promoted the infiltration of B cells through increasing CXCL13 secretion both in vitro experiments and subcutaneous tumor models, thereby amplifying anti-tumor immunity of PD-1 blockade. What was more, we have developed a liposome containing POM-1, which effectively enhanced the anti-tumor effect of POM-1. Our findings provide compelling evidence that targeting CD39 represents a promising "two birds with one stone" strategy for cervical cancer treatment.

Immune-suppressive tumor-associated macrophages (TAMs) that infiltrate the tumor microenvironment (TME), along with the presence of the blood-brain barrier (BBB), influence the effectiveness of immunotherapy for glioblastoma. In this study, we report the use of difluoromethylornithine (DFMO), aPD-L1, and Indocyanine Green (ICG) in combination with target TAMs for their repolarization. DFMO repolarizes TAMs by inhibiting the expression of aconitate decarboxylase 1 (ACOD1), while aPD-L1 blocks the PD-1/PD-L1 immune checkpoint on TAMs, achieving efficient phenotypic switching and enhancing the phagocytic activity against glioblastoma (GBM). When combined with the photothermal agent ICG, the photothermal effect induces immunogenic tumor cell death and further strengthens the repolarization of TAMs. This increases the conversion efficiency of TAMs, reverses immune suppression at the tumor site, and transforms the anti-inflammatory "cold" tumor into a pro-inflammatory "hot" tumor. This approach showed better therapeutic effects in an orthotopic glioma model in mice, with the repolarization of our combined treatment DFMO + N-aP@ICG (nanovesicles containing aPD-L1 and ICG), increasing by 179% compared to other combined treatments for glioma. In summary, we propose this innovative immunotherapy for glioma, which effectively penetrates the blood-brain barrier, targets M2-TAMs, enhances the aPD-L1 immune response, and inhibits the proliferation of glioma.

Fluoxetine, an antidepressant, has shown potential anticancer effects. However, its therapeutic efficacy is limited by its poor bioavailability and rapid metabolism. Nanotechnology is advancing medicine, particularly in developing suitable drug delivery systems to improve therapeutic effects and reduce drug side effects.

Multiple myeloma (MM) ranks second only to lymphoma among hematologic malignancies in terms of incidence. Current treatment methods primarily rely on proteasome inhibitors (PIs) targeting the ubiquitin proteasome system (UPS). However, existing PIs regimens encounter several limitations, including severe adverse effects, rapidly developing resistance during treatment, and restricted therapeutic efficacy. In light of this, our work aims to explore strategies to mitigate poor conditions. We employed a systematic structural optimization process to design and synthesize the new compound BC12-3, based on prevailing PIs. JFCR39 COMPARE analysis was used to assess cytotoxic activity against 39 characteristic cancer cell lines, and the IC50 value of BC12-3 was measured using CCK-8 assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry, while western blotting investigated the antitumor mechanism of BC12-3. In vivo efficacy and safety of BC12-3 and bortezomib (BTZ) were evaluated in the xenograft model. ADMET computational analyses estimated the biological safety of these two inhibitors. As a result, BC12-3 exhibited potent broad-spectrum antitumor activity in vitro particularly against MM cells; This effect was achieved by selectively inhibiting β5 subunit of proteasome activity. BC12-3 suppressed MM cell growth primarily via cell cycle arrest in G2/M phase and apoptosis induction, the related molecular pathways confirmed these phenomena. In vivo studies indicated that BC12-3 exhibits significant effect in inhibiting tumor growth, with its efficacy comparable to that of the standard therapeutic drug, BTZ. Additionally, this new compound showed an excellent safety profile. Consequently, BC12-3 holds promise as a novel therapeutic strategy for the treatment of MM.

To investigate the prevalence and intensity of symptoms in patients with colorectal cancer (CRC), and to develop a symptom network model to pinpoint key symptoms and clusters within the network.

Acute myeloid leukemia (AML) is the most prevalent type of leukemia in adults. Its heterogeneity, both between patients and within the same patient, is often a factor contributing to poor treatment outcomes. Despite advancements in AML biology and medicine in general, the standard AML treatment, the combination of cytarabine and daunorubicin, has remained the same for decades. Combination drug therapies are proven effective in achieving targeted efficacy while minimizing drug dosage and unintended side effects, a common problem for older AML patients. However, a systematic survey of the synergistic potential of drug-drug interactions in the context of AML pathology is lacking. Here, we examine the interactions between 15 commonly used cancer drugs across distinct AML cell lines and demonstrate that synergistic and antagonistic drug-drug interactions are widespread but not conserved across these cell lines. Notably, enasidenib and venetoclax, recently approved anticancer agents, exhibited the highest counts of synergistic interactions and the fewest antagonistic ones. In contrast, 6-Thioguanine, a purine analog, was involved in the highest number of antagonistic interactions. The interactions we report here cannot be attributed solely to the inherent natures of these three drugs, as each drug we examined was involved in several synergistic or antagonistic interactions in the cell lines we tested. Importantly, these drug-drug interactions are not conserved across cell lines, suggesting that the success of combination therapies might vary significantly depending on AML genotypes. For instance, we found that a single mutation in the TF1 cell line could dramatically alter drug-drug interactions, even turning synergistic interactions into antagonistic ones. Our findings provide a preclinical survey of drug-drug interactions, revealing the complexity of the problem.

We introduce click-controlled photouncaging, an innovative approach that synergizes click ligation with photocleavage to achieve biorthogonal, light-triggered bioactive molecule release across visible to near-infrared (NIR) wavelengths. Central to this approach is a novel amine protection and deprotection strategy utilizing Pt(IV) complexes. In this strategy, an azide-bearing clickable Pt(IV) moiety acts as a protecting group for amine-containing molecules (the ″cargo″) via a carbamate linkage. Subsequently, click ligation with a DBCO-tagged fluorescent antenna positions the antenna near the Pt(IV) core, transforming it into a photoactive protecting group (PPG) that can be fine-tuned to respond to visible or NIR light. When exposed to light, the antenna drives the photoreduction of the Pt(IV) linker, triggering deprotection and subsequently releasing the cargo molecule. To validate this approach, three Pt(IV) complexes were synthesized featuring amine-containing fluorescent reporters (coumarin, BODIPY) and a therapeutic molecule (Exatecan), and their functionality was validated in solution and cell cultures. Overall, this work introduces a novel, user-friendly, and versatile chemical tool for bioorthogonal, light-controlled activation of molecules in complex biological environments.

This study investigated the mechanism of Croci Stigma in treating immune checkpoint inhibitor(ICI)-associated myocarditis based on network pharmacology and molecular docking. Network pharmacology was employed to screen the active ingredients and molecular targets of Croci Stigma in treating ICI-associated myocarditis. The "drug-ingredient-target-disease" network and protein-protein interaction network were constructed to screen the key ingredients and core targets. Gene Ontology functional enrichment analysis showed that the mechanism was related to the regulation of inflammation and apoptosis. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the treatment was related to the advanced glycation end product-receptor for advanced glycation end products(AGE-RAGE) signaling pathway. Molecular docking result showed that crocins had close associations with RAC-alpha serine/threonine-protein kinase 1(AKT1), signal transducer and activator of transcription 3, and matrix metalloproteinase 9. Crocins were then selected as the therapeutic drug. The mouse model of ICI-associated myocarditis was established by subcutaneous injection of porcine cardiac myosin combined with intraperitoneal injection of pembrolizumab. The results suggested that Croci Stigma reduced the spleen index but had no effect on the heart index. The electrocardiogram showed that Croci Stigma increased the heart rate and shortened PR and QRS intervals. Echocardiographic data indicated that Croci Stigma increased the left ventricular stroke volume, cardiac output, ejection fraction, and fractional shortening. Hematoxylin-eosin and Masson staining results showed that Croci Stigma decreased the number of inflammatory cells infiltrating in the myocardium and alleviated myocardial fibrosis. Enzyme-linked immunosorbent assay results showed that Croci Stigma decreased the serum levels of inflammatory cytokines including tumor necrosis factor-alpha, interleukin-6, interleukin-12, and regulated on activation, normal T-cell expressed and secreted and lowered the levels of creatine kinase and creatine kinase isoenzyme MB. Biochemical data suggested that Croci Stigma inhibited the activities of superoxide dismutase and lactate dehydrogenase. Western blot result showed that Croci Stigma regulated the expression of myocardial AKT. The findings demonstrate that Croci Stigma may regulate AKT expression to effectively protect the cardiac tissue from ICI-associated myocarditis through antagonizing immune responses and inflammation, inhibiting oxidative stress, alleviating cardiac fibrosis, relieving cardiac block, and improving the cardiac function.

This study primarily investigates the effect of Liuwei Dihuang Pills on the activation and proliferation of female germline stem cells(FGSCs) in the ovaries and cortex of mice with premature ovarian failure(POF), and how it improves ovarian function. ICR mice were randomly divided into the control group, model group, Liuwei Dihuang Pills group, Liuwei Dihuang Pills double-dose group, and estradiol valerate group. A mouse model of POF was established by intraperitoneal injection of cyclophosphamide. After successful modeling, the mice were treated with Liuwei Dihuang Pills or estradiol valerate for 28 days. Vaginal smears were prepared to observe the estrous cycle and body weight. After the last administration, mice were sacrificed and sampled. Serum levels of estradiol(E_2), follicle-stimulating hormone(FSH), luteinizing hormone(LH), and anti-Müllerian hormone(AMH) were measured by enzyme-linked immunosorbent assay(ELISA). Hematoxylin-eosin(HE) staining was used to observe ovarian morphology and to count follicles at all stages to evaluate ovarian function. Immunohistochemistry was used to detect the expression of mouse vasa homolog(MVH), a marker of ovarian FGSCs. Immunofluorescence staining, using co-labeling of MVH and proliferating cell nuclear antigen(PCNA), was used to detect the expression and localization of specific markers of FGSCs. Western blot was employed to assess the protein expression of MVH, octamer-binding transcription factor 4(Oct4), and PCNA in the ovaries. The results showed that compared with the control group, the model group exhibited disordered estrous cycles, decreased ovarian index, increased atretic follicles, and a reduced number of follicles at all stages. FSH and LH levels were significantly elevated, while AMH and E_2 levels were significantly reduced, indicating the success of the model. After treatment with Liuwei Dihuang Pills or estradiol valerate, hormone levels improved, the number of atretic follicles decreased, and the number of follicles at all stages increased. MVH marker protein and PCNA proliferative protein expression in ovarian tissue also increased. These results suggest that Liuwei Dihuang Pills regulate estrous cycles and hormone disorders in POF mice, promote the proliferation of FGSCs, improve follicular development in POF mice, and enhance ovarian function.

Metabolic reprogramming is a hallmark of tumor progression. Here, we examined the metabolic profile of hepatocellular carcinoma (HCC), a disease that responds poorly to immune checkpoint blockade (ICB). Polyamine metabolism increased in HCC samples. Of the polyamine spectrum analyzed, N1-acetylspermidine (N1-Ac-Spd) accumulated in HCC tissue as compared with nontumoral liver tissue and was elevated in paired plasma. Injection of N1-Ac-Spd promoted tumor progression in preclinical models and compromised the efficacy of ICB. Inflammatory macrophages increased expression of the spermidine/spermine N1-acetyltransferase 1, SAT1, in hepatoma cells, leading to increased N1-Ac-Spd efflux via the polyamine transporter protein SLC3A2. Mechanistically, N1-Ac-Spd efflux activated SRC signaling in a charge-dependent manner, which in turn induced CCL1+ macrophage polarization, the recruitment of CCR8+ regulatory T cells, and an immunosuppressive tumor microenvironment (TME). In vivo interventions targeting SLC3A2, SAT1, or CCL1 enhanced the antitumor effects of ICB therapy. Our findings provide insight into the mechanisms whereby metabolic reprogramming fosters an immunosuppressive TME, with implications for the treatment of HCC.

The lack of T cells in tumors is a major hurdle to successful immune checkpoint therapy (ICT). Therefore, therapeutic strategies promoting T cell recruitment into tumors are warranted to improve the treatment efficacy. Here, we report that Fc-optimized anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are potent remodelers of tumor vasculature that increase tumor-associated high endothelial venules (TA-HEVs), specialized blood vessels supporting lymphocyte entry into tumors. Mechanistically, this effect is dependent on the Fc domain of anti-CTLA-4 antibodies and CD4+ T cells and involves interferon gamma (IFNγ). Unexpectedly, we find that the human anti-CTLA-4 antibody ipilimumab fails to increase TA-HEVs in a humanized mouse model. However, increasing its Fc effector function rescues the modulation of TA-HEVs, promotes CD4+ and CD8+ T cell infiltration into tumors, and sensitizes recalcitrant tumors to programmed cell death protein 1 (PD-1) blockade. Our findings suggest that Fc-optimized anti-CTLA-4 antibodies could be used to reprogram tumor vasculature in poorly immunogenic cold tumors and improve the efficacy of ICT.

Ferroptosis serves as a pivotal mechanism in diverse clinical chemotherapeutics and physiological processes, profoundly impacting tumor metabolism and the tumor microenvironment. Recently, the immunosuppression induced by ferroptosis has raised major concerns regarding tumor recurrence upon ferroptosis-based antitumor therapies. However, due to the lack of cell specificity, the antitumor and immunosuppressive effects in ferroptosis are inherently intertwined. Herein, we address the conflicting challenges between immunosuppression and antitumor efficacy in ferroptosis-based therapy by enabling cell-specific ferroptosis, thereby targeting tumors while sparing immune cells. By employing a specially designed nanoagent, i.e., ferrous selenide half-shell-covered gold, we induce notable upregulation of glutathione peroxidase 4 (GPX4) and downregulation of prostaglandin E2, leading to an increase in CD4+ and CD8+ T cell populations and intense antitumor immune responses. Despite the elevated level of GPX4, significant tumor cell ferroptosis is achieved, which is further promoted by the agent's photothermal and photocatalytic effects. Consequently, long-term immunological memory is established, yielding a long-lasting and recurrence-free antitumor efficacy spanning at least 200 days post-treatment. This work unlocks an avenue to balance immunosuppression reversal with tumor inhibition in ferroptosis-based therapies, providing promising prospects for antitumor therapies facing immunological hurdles in the tumor microenvironment.

Antibody-drug conjugates (ADCs) have emerged as a highly promising modality for the treatment of various tumors, including pancreatic cancer. Due to the modular nature of ADCs, their efficacy is heavily influenced by the choice of antibody, payload, and linker. Given the therapeutic potential of triptolide for pancreatic cancer, this study aims to harness triptolide as the cytotoxic payload to construct ADCs targeting pancreatic cancer. Silyl ethers were utilized for the first time as cleavable linkers to connect triptolide with an antibody. This is because silyl ethers can be easily synthesized and the rate of drug release can be regulated by modifying the silyl ether groups. The release profile of the resulting linkers was investigated. And considering the balance between cleavage and stability, one silyl ether-based linker was selected to prepare an ADC, named A10. Meanwhile, a traditional dipeptide linker-based ADC, A9, was synthesized for comparison. The ADC A10 demonstrated superior inhibitory effects compared to ADC A9, both in vitro and in vivo. A10 displayed targeted cytotoxicity against cells with high PD-L1 expression and demonstrated a bystander killing effect on cells with low PD-L1 expression. In vivo imaging studies indicated that fluorescently labeled A10 accumulated in tumor regions. Additionally, significant antitumor activities of A10 were observed against Panc 08.13-derived tumor xenografts.

Protein deubiquitination via deubiquitinases is a crucial aspect of the dynamic modification of biomacromolecules. The deubiquitinase USP7 plays a key role in tumorigenesis through diverse pathways, thus representing a promising novel target for anti-cancer therapies. In this paper, in order to find novel USP7 inhibitors, a series of compounds scaffold-hopping from the reported USP7 inhibitor CP41 were designed, synthesized and biologically evaluated. Most of them exhibited certain inhibition against the in vitro USP7 enzyme activity. The most potent compounds (X12, X16, X21, X22 and X23) were highly selective for USP7 over a panel of other tested DUBs and showed significant in vitro inhibition against cancer cell proliferation. Interestingly, in RS4; 11 cancer cells, the selected compound X21 not only regulated the level of the extensively studied proteins (e.g. MDM2, p53, TRIM27) but also remarkably reduced the protein level of PCLAF, a key factor involved in TLS. In colon cancer animal models, X21 exerted in vivo anti-tumor efficacy, probably through synergistic effects of direct cytotoxicity and immune microenvironment improvement. These findings may provide directions for future design of novel USP7 inhibitors and facilitate the exploration of new mechanism of USP7 inhibitors.

S-phase kinase-associated protein 2 (Skp2) is the vital component of the Skp1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complex, which precisely regulates CDK inhibitors by coordinating with Cks1 and has been identified to be involved in the progression of many human malignancies. Inspired by our previous study, we designed novel 2,3-diarylpyrazine derivatives via molecular hybridization strategy to enhance Skp2-Cks1 inhibition. Compound 10h emerged as the most potent inhibitor, displaying an IC50 value of 0.38 μM against Skp2-Cks1 binding with 7.3- and 12.8-fold improvements over leads ZK-14i and HK-E35, respectively. Moreover, 10h demonstrated excellent anti-tumor activities against lung cancer NCl-H1299 and esophageal cancer KYSE-510 cells, inducing S-phase arrest and suppressing proliferation through targeting Skp2. Notably, 10h significantly increased the sensitivity of NCl-H1299 cells to cisplatin by suppressing the cell stemness. Overall, this study developed 10h as a potent Skp2 inhibitor and explored its effects on tumor treatment, especially in enhancing the efficacy of cisplatin during chemotherapy.

Sarcoidosis is a multisystemic granulomatous disease of uncertain etiology. Several drugs have been linked to the development of sarcoidosis or systemic granulomatous reactions indistinguishable from this disease. We present the clinical case of a patient diagnosed with breast cancer and undergoing treatment with capecitabine who, after developing systemic and musculoskeletal symptoms, was ultimately diagnosed with capecitabine-induced sarcoidosis.

Multidrug resistance (MDR) is one of the major problems in cancer treatment. Overcoming MDR to achieve effective cancer treatment remains a huge challenge. Here, we proposed a self-generative singlet oxygen (1O2)-initiated chemical modification of nuclear DNAs (SiCMoND) approach to kill multidrug-resistant tumor synergizing with chemotherapy. A tumor-targeted "nano-bomb" FA(CT-fT-Dox) was rationally fabricated by encapsulating the complex of Cu2+ with tetrakis(4-carboxyphenyl) porphyrin) (Cu-TCPP) as a 1O2 generator and a doxorubicin (Dox) prodrug tailed with a furan-containing positively charged peptide (fTAT-Dox) within the micelles of FA-PEG5000-PCL3000 and mPEG5000-PCL3000. When FA(CT-fT-Dox) nanoparticles accumulated at the tumor site, they could undergo disassembly in the tumor microenvironment (TME) specifically to release Cu-TCPP and fTAT-Dox simultaneously. Taking advantage of the features of Cu-TCPP that can convert tumor-abundant H2O2 into 1O2 and fTAT-Dox that can readily penetrate the cell membrane into the nucleus, chemical modification of nuclear DNAs was realized through the covalent cyclization reaction between furan and nucleobases of nuclear DNAs under the ignition of self-generative 1O2, which leads to significant DNA damage and enhanced therapeutic susceptibility. More notably, the sustained release of Dox within the nucleus greatly inhibits DNA transcription and translation leading to severe cancer cell apoptosis. In vivo studies in a multidrug-resistant MCF-7/ADR tumor model showed that the antitumor efficacy of FA(CT-fT-Dox) was 1.6-fold higher than FA(CT-T-Dox) without DNA modification functionality with a tumor suppression efficiency of 83.3%. This SiCMoND-assisting chemotherapy strategy provides a promising antitumor therapeutic modality and opens new avenues for battling multidrug-resistant tumors.