Cisplatin is a platinum-based drug that is frequently used to treat multiple tumors. The anti-tumor effect of cisplatin is closely related to the tumor immune microenvironment (TIME), which includes several immune cell types, such as the tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and natural killer (NK) cells. The interaction between these immune cells can promote tumor survival and chemoresistance, and decrease the efficacy of cisplatin monotherapy. Therefore, various combination treatment strategies have been devised to enhance patient responsiveness to cisplatin therapy. Cisplatin can augment anti-tumor immune responses in combination with immune checkpoint blockers (such as PD-1/PD-L1 or CTLA4 inhibitors), lipid metabolism disruptors (like FASN inhibitors and SCD inhibitors) and nanoparticles (NPs), resulting in better outcomes. Exploring the interaction between cisplatin and the TIME will help identify potential therapeutic targets for improving the treatment outcomes in cancer patients.

The lung tumour microenvironment (TME) is composed of various cell types, including cancer cells, stromal and immune cells, as well as extracellular matrix (ECM). These cells and surrounding ECM create a stiff, hypoxic, acidic and immunosuppressive microenvironment that can augment the resistance of lung tumours to different forms of cell death and facilitate invasion and metastasis. This environment can induce chemo/radiotherapy resistance by inducing anti-apoptosis mediators such as phosphoinositide 3-kinase (PI3K)/Akt, signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB), leading to the exhaustion of antitumor immunity and further resistance to chemo/radiotherapy. In addition, lung tumour cells can resist chemo/radiotherapy by boosting multidrug resistance mechanisms and antioxidant defence systems within cancer cells and other TME components. In this review, we discuss the interactions and communications between these different components of the lung TME and also the effects of hypoxia, immune evasion and ECM remodelling on lung cancer resistance. Finally, we review the current strategies in preclinical and clinical studies, including the inhibition of checkpoint molecules, chemoattractants, cytokines, growth factors and immunosuppressive mediators such as programmed death 1 (PD-1), insulin-like growth factor 2 (IGF-2) for targeting the lung TME to overcome resistance to chemotherapy and radiotherapy.

Intrahepatic cholangiocarcinoma (ICC) ranks second among primary liver cancers in terms of prevalence, characterized by poor prognosis and scarce therapeutic interventions. Fufang-Biejia-Ruangan tablet (BJRG), a traditional Chinese herbal remedy, has been widely used for liver diseases. However, its therapeutic efficacy and underlying mechanisms in ICC remain poorly understood.

This study aims to systematically investigate the anti-ICC effects of BJRG, focusing on tumor progression and microenvironment modulation, through experimental and transcriptomic analyses.

The chemical composition of BJRG was analyzed employing ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). In vitro assays were performed with QBC939 and LX-2 cell lines. Two primary ICC models (AKT/YAP and sgP53/KRAS) were established via hydrodynamic tail-vein injection of corresponding plasmids. A co-culture system for subcutaneous tumor formation was developed using cancer-associated fibroblasts (CAFs) derived from the AKT/YAP model and primary tumor cells derived from the sgP53/KRAS model.

UPLC-MS analysis identified 1091 chemical components, primarily terpenoids, sugars, glycosides, and phenylpropanoids. The therapeutic efficacy of BJRG was evaluated for the treatment of ICC. BJRG treatment slowed down the growth of both human ICC cell lines and AKT/YAP ICC mouse model. Mechanistically, BJRG inhibited HIPPO-PI3K/AKT signaling pathway in ICC tumor cells. Importantly, BJRG significantly inhibited the growth of CAFs via HIPPO-PI3K/AKT cascades. Of note, co-culture CAFs with ICC cell lines substantially sensitized the efficacy of BJRG in sgP53/KRAS syngeneic tumor model. Furthermore, BJRG therapy not only affected CAFs but also induced alterations in vascular structures and hypoxic conditions within lesions in the AKT/YAP model. This intervention promoted the infiltration of T lymphocytes and macrophages into the tumor microenvironment, which may further augment the anti-proliferative effects of BJRG by enhancing the immune response within ICC tumor tissues.

Our research demonstrates BJRG's anti-ICC efficacy via diverse pathways, including the suppression of tumor cell proliferation, regulation of CAFs activity, and promotion of immune cell infiltration. These findings underscore BJRG as a promising therapeutic candidate for ICC, offering novel mechanistic insights and highlighting its potential for clinical translation.

The stimulator of interferon genes (STING) signaling pathway has been demonstrated to propagate the cancer-immunity cycle and remodel the tumor microenvironment and has emerged as an appealing target for cancer immunotherapy. Interest in STING agonist development has increased, and the candidates hold significant promise; however, most are still in the early stages of human clinical trials. We found that ABT-199 activated the STING pathway to enhance the immunotherapeutic effect, and provided a ready-to-use small molecule drug for STING signaling activation.

Phosphorylation of STING, TBK1, and IRF3, as well as activation of the interferon-I (IFN-I) signaling pathway, were detected following ABT-199 treatment in various colorectal cancer cells. C57BL/6J and BALB/c mice with subcutaneous tumors were employed to evaluate the in vivo therapeutic effects of the ABT-199 and anti-PD-L1 combination. Flow cytometry and ELISA were employed to analyze the level and activity of tumor-infiltrating T lymphocytes. Immunofluorescence and quantitative real-time PCR were conducted to assess the source and accumulation of double stranded DNA (dsDNA) in the cytoplasm. Chemical cross-linking assay, co-immunoprecipitation, and CRISPR/Cas9-mediated knockout were performed to investigate the molecular mechanism underlying ABT-199-induced voltage-dependent anion channel protein 1 (VDAC1) oligomerization and mitochondrial DNA (mtDNA) release.

ABT-199 significantly activated the STING signaling pathway in various colorectal cancer cells, which was evidenced by increased phosphorylation of TBK1 and IRF3, and upregulation of C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 10 (CXCL10), and interferon beta transcription. By promoting chemokine expression and cytotoxic T-cell infiltration, ABT-199 promoted antitumor immunity and synergized with anti-PD-L1 therapy to improve antitumor efficacy. ABT-199 induced mtDNA accumulation in the cytoplasm and triggered STING signaling via the canonical pathway. cGAS or STING-KO models significantly abolished both STING signaling activation and the antitumor efficacy of ABT-199. Mechanically, ABT-199 promoted VDAC1 oligomerization by disturbing the binding between BCL-2 and VDAC1, thereby facilitating mtDNA release into the cytoplasm. ABT-199-triggered STING signaling was attenuated when VADC1 was knocked out. Consistently, the antitumor effect of ABT-199 in vivo was abolished in the absence of VDAC1.

Our results identify a ready-to-use small molecule compound for STING activation, reveal the underlying molecular mechanism through which ABT-199 activates the STING signaling pathway, and provide a theoretical basis for the use of ABT-199 in cancer immunotherapy.

Chemotherapy combined with anti-angiogenic therapy has become an important strategy for the treatment of advanced gastric cancer (AGC); however, the regimen needs optimization.

To evaluate the efficacy of albumin-bound paclitaxel (nab-ptx) combined with the small molecule vascular endothelial growth factor inhibitor anlotinib in second-line and beyond treatment of AGC.

We collected data from AGC patients at our hospital who experienced disease progression after first-line chemotherapy and received anlotinib combined with nab-ptx. The primary endpoints included overall survival (OS) and progression-free survival (PFS), while the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and adverse events (AEs).

Preliminary results indicated that anlotinib combined with nab-ptx can provide significant efficacy in second-line or above treatment for AGC (median PFS = 6.0 months, median OS = 12.0 months), with an ORR of 42% and a DCR of 78%. Further analysis revealed that patients who experienced hypertension, proteinuria, and hand-foot syndrome during treatment had better efficacy compared to those who did not experience these AEs. Mechanistic studies suggest that this regimen likely exerts synergistic anti-tumor effects by activating the immune response through the reduction of regulatory T-cell proportions. Common adverse reactions included bone marrow suppression, peripheral neuropathy, hypertension, proteinuria, and hand-foot syndrome, which were manageable and resolved with appropriate interventions, indicating the promising application of this regimen in second-line or above treatment for AGC.

The combination of anlotinib and nab-ptx shows promising efficacy with fewer toxicities in AGC treatment. The regimen holds promise as a second-line treatment of AGC; however, its specific clinical value requires further research.

Given the limited efficacy of current first-line therapies, there is an urgent need to develop novel treatment strategies to improve the prognosis of patients with unresectable intrahepatic cholangiocarcinoma (uICC). This study aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimens (HAIC-FO) plus anti-programmed death-(ligand) 1 immunotherapy [αPD-(L)1] antibody [HAIC+αPD-(L)1] compared to systemic chemotherapy (SYS) plus αPD-(L)1 antibody [SYS+αPD-(L)1] as a first-line treatment for patients with uICC.

In this retrospective study, treatment-naive uICC patients who were treated with HAIC+αPD-(L)1 or SYS+αPD-(L)1 were included. The clinical characteristics, therapeutic outcomes, and adverse events (AEs) of the patients in the two groups were compared. Propensity score matching (PSM) was performed to minimize biases between groups.

From January 2019 to January 2023, a total of 182 patients were enrolled; 147 patients were included in the HAIC+αPD-(L)1 group and 35 patients were included in the SYS+αPD-(L)1 group. After PSM, 61 and 26 patients were included in the HAIC+αPD-(L)1 and SYS+αPD-(L)1 groups, respectively. The HAIC+αPD-(L)1 group had longer median overall survival (mOS), median progression-free survival (mPFS), and median intrahepatic PFS (mIPFS) than did the SYS+αPD-(L)1 group (mOS: 14.5 vs. 10.5 months, P=0.02; mPFS: 10.4 vs. 6.4 months, P=0.02; mIPFS: 11.4 vs. 6.5 months, P<0.001). The overall incidence of AEs was comparable between the two groups, but the HAIC+αPD-(L)1 group had a lower incidence of grade 3-4 AEs related to anemia, leukopenia, weight loss, and fatigue.

HAIC+αPD-(L)1 had acceptable toxic effects and might improve outcomes compared to SYS+αPD-(L)1 as a first-line treatment for patients with uICC.

Globally, non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths. Rutecarpine (RUT), a quinazolinocarboline alkaloid that is naturally occurring and present in Chinese medicinal herbs, has been shown to have anticancer properties in several cancer cell lines. However, the specific antitumor mechanisms of RUT in NSCLC remain unclear. This study demonstrates that RUT induces apoptosis and significantly reduces the viability of NSCLC cell lines. This effect is achieved by stimulating intracellular ROS production, leading to mitochondrial dysfunction. The decreased cell viability observed with RUT treatment is attributed to the elimination of ROS and apoptosis through the suppression of ROS by N-acetylcysteine (NAC). Furthermore, RUT therapy elevated the production of CXCL10 and CCL5 in NSCLC cell lines and markedly activated the STING pathway in NSCLC cells. Mechanistically, RUT substantially decreased the levels of PD-L1 protein in NSCLC cells. Notably, in vivo experiments demonstrated that RUT significantly inhibits mouse NSCLC tumor growth in mice, exhibiting anti-tumor activity by elevating CD8+ T cells. These findings strongly support RUT as a promising anti-cancer drug for NSCLC.

The aim of the present study was to investigate the efficacy and safety of anlotinib combined with vinorelbine (NVB) as a second-line treatment for elderly patients with advanced squamous cell lung carcinoma (SqCLC). The present retrospective analysis included 48 elderly patients (aged ≥65 years) diagnosed with advanced SqCLC who received anlotinib in combination with NVB as a second-line therapy between January 2021 and December 2023. The primary endpoints assessed were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety profile. The median PFS and OS for the cohort was found to be 5.0 and 9.5 months, respectively. By contrast, the ORR and DCR were found to be 29.17 and 70.83%. Further subgroup analysis indicated that patients who experienced specific adverse events (AEs), such as hypertension, proteinuria and hand-foot syndrome during treatment, generally had superior efficacy compared with those who did not experience these AEs (mPFS, 6.0 vs. 4.0 months; mOS, 11.0 vs. 8.5 months). In addition, apart from promising efficacy, patients who experienced common AEs also experienced decreased appetite (35.42%), fatigue (29.17%), hypertension (25%) and hand-foot syndrome (27.08%). Grade 3 or higher AEs occurred in <30% of patients, the majority of which was alleviated through corresponding support care. These results suggest that the combination of anlotinib and NVB as second-line therapy for elderly patients with advanced SqCLC demonstrated promising efficacy and a manageable safety profile. Such regimen may be a viable treatment option for this patient population. However, further prospective studies are required to validate these findings and optimize the dosing schedule for improved therapeutic outcomes.

To develop personalized treatment strategies for maintenance therapy in patients with extensive-stage small cell lung cancer (ES-SCLC).

We analyzed data from ES-SCLC patients who achieved stable disease (SD) following initial chemotherapy combined with immunotherapy. These patients subsequently received maintenance therapy (MT) with a combination of anlotinib and PD-1/L1 inhibitors. The primary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs).

Preliminary findings suggest that this regimen is highly effective, with a median PFS of 6 months and OS of 13.5 months, alongside a DCR exceeding 60%. Subgroup analysis revealed enhanced efficacy in patients with fewer than three metastatic sites and those who experienced hypertension, proteinuria, or hand-foot syndrome during MT. Mechanistic studies showed a notable increase in the proportion of CD8+ T cells in the peripheral blood post-MT, correlating with improved outcomes. These findings imply that the therapeutic effect of MT may be partly due to the direct activation of CD8+ T cells, producing a synergistic anti-tumor response. Despite the prevalence of AEs, AEs were generally manageable, underscoring anlotinib's potential in this context.

The combination of anlotinib and PD-1/L1 inhibitors offers promising efficacy and manageable AEs in MT, making it a viable option for ES-SCLC patients who achieve SD post-initial therapy. These results justify further prospective studies to validate this approach.

The Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes [1] signaling pathway has emerged as a pivotal immune response mechanism, activating immune defenses upon detection of both exogenous and endogenous DNA within cells. Its activation is intricately linked to various diseases and inflammatory processes, spanning autoimmune disorders, infectious ailments, and malignancies. Among pancreatic diseases, encompassing acute pancreatitis, chronic pancreatitis, and pancreatic cancer, current clinical treatment efficacy remains suboptimal. Here, we elucidate the molecular intricacies of the cGAS-STING signaling pathway and delineate its therapeutic potential in acute pancreatitis, chronic pancreatitis, and pancreatic cancer. Additionally, we offer an overview of recent advancements in STING agonists and antagonists, assessing their therapeutic potential in pancreatic-related disorders. In summary, by exploring the multifaceted roles of the cGAS-STING signaling pathway and its implications in pancreatic diseases, we aim to shed light on potential avenues for therapeutic intervention and management in these challenging clinical contexts.

Extensive-stage small cell lung cancer (ES-SCLC) suffering from brain metastases (BM) has a poor prognosis and lacks effective treatment selection. In this study, we explored the efficacy and safety of combination treatment of albumin-bound paclitaxel (nab-ptx), anlotinib, and PD-1/L1 inhibitors for such special population.

A total of 55 patients diagnosed with ES-SCLC and BM were enrolled in this retrospective study. Patients received a combination therapy consisting of nab-ptx, anlotinib, and PD-1/L1 inhibitors. The primary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).

The results demonstrated promising efficacy of the combination therapy for such patients, with an ORR of 36.36%, median PFS and OS of 5.0 and 10.0 m, correspondingly. Subgroup analyses indicated that treatment efficacy closely correlated with patients' Ds-GPA (Diagnosis-specified Graded Prognosis Assessment) scores. Mechanistic studies revealed that this regimen likely operates by reducing immune suppression to activate immune function, thereby exerting synergistic anti-tumor effects. The common AEs include decreased appetite, nausea, leukopenia, hypertension, proteinuria, hand-foot syndrome, peripheral neuropathy, rash, and thyroid toxicity, most of which are generally mild and can be alleviated with symptomatic treatment.

The combination of nab-ptx, anlotinib, and PD-1/L1 inhibitors exhibited substantial efficacy and acceptable safety in the treatment of BM from ES-SCLC. This novel therapeutic approach holds promise for improving the outcomes for patients with this challenging disease. Further studies are needed to validate these findings and investigate the long-term benefits of this combination regimen.

Bladder cancer (BCa) is the 10th most prevalent cancer globally. Neoadjuvant therapy has become the standard treatment for muscle-invasive bladder cancer, yet the pathologic complete response rate for patients is only approximately 35%. However, the mechanisms underlying neoadjuvant therapy resistance in bladder cancer patients remain unclear. We collected two sets of paired bladder cancer specimens before and after neoadjuvant therapy, and performed RNA sequencing. The findings revealed a significant decrease in IFI27 expression levels in the post-neoadjuvant therapy group compared to samples collected before treatment, suggesting that IFI27 may play a role in resistance to neoadjuvant combination therapy. IFI27, a member of the interferon-alpha (IFN-α) inducible gene family, influences the efficacy of immune checkpoint blockade therapy. Further analysis demonstrated that IFI27 is predominantly expressed in the cytoplasm of bladder cancer cells and exhibited low expression levels in bladder cancer tissues and cell lines. Subsequently, we investigated the inhibitory effects of IFI27 on bladder cancer proliferation, migration, epithelial-mesenchymal transition, and lymph node metastasis. Additionally, in a mouse model, PD-1Ab immunotherapy was found to upregulate IFI27 while downregulating the protein level of FOXP3, a key transcription factor for regulatory T cells. Flow cytometric analysis further demonstrated that IFI27 inhibits bladder cancer progression by suppressing regulatory T cell infiltration and enhancing anti-tumor immune responses. In conclusion, these findings establish IFI27 as a promising molecular marker for improving the efficacy of immunotherapy in bladder cancer and offer valuable insights into strategies for enhancing immunotherapy sensitivity.

Chemotherapy including platinum-based drugs are a possible strategy to enhance the immune response in advanced melanoma patients who are resistant to immune checkpoint blockade (ICB) therapy. However, the immune-boosting effects of these drugs are a subject of controversy, and their impact on the tumor microenvironment are poorly understood. In this study, we discovered that lipid peroxidation (LPO) promotes the formation of lipid rafts in the membrane, which mediated by Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) impairs the sensitivity of melanoma cells to platinum-based drugs. This reduction primarily occurs through the inhibition of immunogenic ferroptosis and pyroptosis by reducing cell membrane pore formation. By disrupting ACSL4-mediaged lipid rafts via the removal of membrane cholesterol, we promoted immunogenic cell death, transformed the immunosuppressive environment, and improved the antitumor effectiveness of platinum-based drugs and immune response. This disruption also helped reverse the decrease in CD8+ T cells while maintaining their ability to secrete cytokines. Our results reveal that ACSL4-dependent LPO is a key regulator of lipid rafts formation and antitumor immunity, and that disrupting lipid rafts has the potential to enhance platinum-based drug-induced immunogenic ferroptosis and pyroptosis in melanoma. This novel strategy may augment the antitumor immunity of platinum-based therapy and further complement ICB therapy.

The efficacy of PD-1 therapy in non-small cell lung cancer (NSCLC) patients remains unsatisfactory. Activating the STING pathway is a promising strategy to improve PD-1 inhibitor efficacy. Here, we found tetrandrine (TET), an anti-tumor compound extracted from a medicinal plant commonly used in traditional Chinese medicine, has the ability to inhibit NSCLC tumor growth. Mechanistically, TET induces nuclear DNA damage and increases cytosolic dsDNA, thereby activating the STING/TBK1/IRF3 pathway, which in turn promotes the tumor infiltration of dendritic cells (DCs), macrophages, as well as CD8+ T cells in mice. In vivo imaging dynamically monitored the increased activity of the STING pathway after TET treatment and predicted the activation of the tumor immune microenvironment. We further revealed that the combination of TET with αPD-1 monoclonal antibody (αPD-1 mAb) yields significant anti-cancer effects by promoting CD8+ T cell infiltration and enhancing its cell-killing effect, which in turn reduced the growth of tumors and prolonged survival of NSCLC mice. Therefore, TET effectively eliminates NSCLC cells and enhances immunotherapy efficacy through the activation of the STING pathway, and combining TET with anti-PD-1 immunotherapy deserves further exploration for applications.

Existing research data indicates that albumin-bound paclitaxel (nab-ptx), anlotinib, and PD-1/L1 inhibitors have individually shown efficacy in second-line and subsequent treatments for advanced non-small cell lung cancer (NSCLC). This study seeks to investigate the potential of an optimized treatment regimen in this context by combining these three drugs and evaluating both efficacy and safety outcomes.

Between January 2020 and January 2022, we collected data from pre-treated advanced NSCLC patients who received a combination therapy of nab-ptx, anlotinib, and PD-1/L1 inhibitors as a second-line or later treatment. The primary endpoints for the study included the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR) and overall survival (OS), while adverse events (AEs) were also recorded.

Our findings revealed that the ORR of this regimen in pretreated NSCLC patients was 35.71%, with mean PFS of 5.0 months and mean OS of 10.0 months. Further analysis suggested correlations between the efficacy of the regimen and factors such as PD-L1 expression levels, the occurrence of certain types of adverse events, and the status of NK cell activity. Additionally, the tolerable toxicity profile of this regimen indicates its potential applicability in the treatment of pretreated advanced NSCLC.

Our study displayed that triple-drug combination of nab-ptx, anlotinib and PD-1/L1 inhibitors showed promising efficiency and tolerated cytotoxicity in the 2nd or above line treatment of advanced NSCLC, indicating the potential of such regimen as an important option for second-line treatment of advanced NSCLC. However, due to limitations in patient numbers, its actual clinical value awaits further research confirmation.

With the advancing comprehension of immunology, an increasing number of immunotherapies are being explored and implemented in the field of cancer treatment. The cGAS-STING pathway, a crucial element of the innate immune response, has been identified as pivotal in cancer immunotherapy. We evaluated the antitumor effects of Schisandra chinensis lignan component Schisandrin C (SC) in 4T1 and MC38 tumor-bearing mice, and studied the enhancing effects of SC on the cGAS-STING pathway and antitumor immunity through RNA sequencing, qRT-PCR, and flow cytometry. Our findings revealed that SC significantly inhibited tumor growth in models of both breast and colon cancer. This suppression of tumor growth was attributed to the activation of type I IFN response and the augmented presence of T cells and NK cells within the tumor. Additionally, SC markedly promoted the cGAS-STING pathway activation induced by cisplatin. In comparison to cisplatin monotherapy, the combined treatment of SC and cisplatin exhibited a greater inhibitory effect on tumor growth. The amplified chemotherapeutic efficacy was associated with an enhanced type I IFN response and strengthened antitumor immunity. SC was shown to reduce tumor growth and increase chemotherapy sensitivity by enhancing the type I IFN response activation and boosting antitumor immunity, which enriched the research into the antitumor immunity of S. chinensis and laid a theoretical basis for its application in combating breast and colon cancer.

Reactive oxygen species (ROS) in biological systems are transient but essential molecules that are generated and eliminated by a complex set of delicately balanced molecular machineries. Disruption of redox homeostasis has been associated with various human diseases, especially cancer, in which increased ROS levels are thought to have a major role in tumour development and progression. As such, modulation of cellular redox status by targeting ROS and their regulatory machineries is considered a promising therapeutic strategy for cancer treatment. Recently, there has been major progress in this field, including the discovery of novel redox signalling pathways that affect the metabolism of tumour cells as well as immune cells in the tumour microenvironment, and the intriguing ROS regulation of biomolecular phase separation. Progress has also been made in exploring redox regulation in cancer stem cells, the role of ROS in determining cell fate and new anticancer agents that target ROS. This Review discusses these research developments and their implications for cancer therapy and drug discovery, as well as emerging concepts, paradoxes and future perspectives.

Basement membrane-related genes (BMs) participate in regulating cell polarity, invasion, metastasis, and survival across different tumor types. Nevertheless, the specific functions of BMs in colorectal cancer (CRC) remain uncertain.

To investigate the clinical relevance of BMs in CRC, we retrieved both gene expression and clinical data from The Cancer Genome Atlas (TCGA) datasets for subsequent analysis. The Kaplan-Meier (K-M) survival curve was employed to evaluate prognosis in high- and low-risk groups. Furthermore, additional analyses, including nomogram construction, functional enrichment, examination of the tumor immune microenvironment, prediction of small-molecule drugs, and more, were conducted to delve into the significance of BM-related signatures in CRC. Single-cell data from seven CRC patients were obtained from the TISCH2 database, and expression validation and cell source exploration of BM-related signatures were performed. Lastly, the expression and function of TIMP1, a key gene in BMs that may play a role in the progression of CRC, was validated in vitro through a series of basic experiments.

We constructed a seven BMs-based model to categorize CRC patients into high-risk and low-risk groups. K-M survival analysis indicated a poorer prognosis for high-risk CRC patients. Cox regression analysis further identified the risk score as an independent prognostic factor for CRC patients. The nomogram model exhibited superior discrimination and calibration abilities of CRC patients. Based on the results from GO/KEGG and GSEA, genes in the high-risk subgroup were implicated in immune-related pathways and exhibited a positive correlation with immune checkpoints. In single-cell data, we found that TIMP1 is highly expressed in many cells, especially in malignant tumor cells. We also observed up-regulation of TIMP1 in CRC cell lines, promoting cancer invasion and migration in vitro.

Our study has discovered a novel prognostic index derived from BM-related genes in CRC patients. Specifically, the new model enables patient stratification, improving the selection of individuals likely to benefit from immunotherapy.

Hepatocellular carcinoma, characterized by high mortality rates, often exhibits limited responsiveness to conventional treatments such as surgery, radiotherapy, and chemotherapy. Therefore, identifying a sensitizer for cisplatin has become crucial. Dihydroartemisinin, known for its potent role of tumor treatment, arises as a prospective candidate for cisplatin sensitization in clinical settings.

A mouse model of liver tumor was established through chemical induction of DEN/TCPOBOP. Upon successful model establishment, ultrasound was employed to detect tumors, Hematoxylin and eosin staining was conducted for observation of liver tissue pathology, and ELISA was utilized to assess cytokine changes (IFN-γ, IL-2, IL-4, IL-10, TGF-β, IL-1β, CCL2, and CCL21) in peripheral blood, para-tumor tissues, and tumor tissues. The infiltration of CD8+T cells and macrophages in tumor tissue sections was detected by immunofluorescence.

Dihydroartemisinin combined with cisplatin obviously restrained the growth of liver tumors in mice and improved the weight and spleen loss caused by cisplatin. Cisplatin treatment of liver tumor mice increased the content of CCL2 and the number of macrophages in tumor tissues and promoted the formation of an immunosuppressive microenvironment. The combination therapy decreased the content of TGF-β in tumor tissues while increasing CCL2 levels in para-tumor tissues. Both combination therapy and cisplatin alone increased the number of CD8+T cells in tumor tissue, but there was no difference between them.

Dihydroartemisinin combined with cisplatin obviously prevented the deterioration of liver tumor in hepatocellular carcinoma mice and improve the therapeutic effect of cisplatin by improving the immunosuppressive microenvironment induced by cisplatin. Our findings provide a theoretical basis for considering dihydroartemisinin as an adjuvant drug for cisplatin in the treatment of hepatocellular carcinoma in the future.

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity. ONC201 is a dual PI3K/AKT and MEK pathway inhibitor with an excellent safety profile that targets death receptor 5 (DR5) to induce apoptosis. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable and can be stabilized by a prodrug approach. In this study, phospho-Akt, phospho-mTOR, and phospho-ERK protein expressions were evaluated in patient PDAC-tissues (n = 10). We used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. Further, we evaluated the efficacy of L_GEM and ONC201 in PC cells and "KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. PDAC patient tissues showed significantly higher levels of p-AKT (Ser473), p-ERK (T202/T204), and p-mTOR compared to surrounding non-cancerous tissues. ONC201 in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. In our in-vivo study, we found that ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade to overcome chemoresistance and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.

So far, the treatment options for most advanced non-small cell lung cancer (NSCLC) with brain metastasis have been limited. Apatinib, an oral tyrosine kinase inhibitor (TKI) with anti-angiogenesis properties, has been approved for advanced gastric cancer in China. Clinical studies have demonstrated that apatinib also displays anticancer effects against several other human cancers, including NSCLC. We have observed that apatinib combined with pemetrexed or docetaxel shows promising efficiency for advanced NSCLC patients who have previously undergone two or more lines of treatment, we would like to further perform a retrospective efficiency analysis of apatinib combined with pemetrexed or docetaxel in advanced NSCLC patients with multiple brain metastasis in this study.

A total of 35 patients, between 18 and 70 years old, who were clinically and pathologically confirmed as having advanced NSCLC were included in this study. All of the included patients had accepted two or more lines of treatment. These patients received apatinib combined with pemetrexed or docetaxel between January 2014 and November 2020 in Hubei Cancer Hospital.

The results showed that apatinib combined with pemetrexed or docetaxel could effectively delay the disease progression of brain metastasis in advanced NSCLC, with an approximate overall response rate (ORR) for measurable and non-measurable lesions of 10% and 15%, respectively. The disease control rate (DCR) for intracranial lesions was 66%, the median progression-free survival (PFS) was 4.0 months, and the median overall survival (OS) was 9.0 months. The most common treatment-related toxicities, such as fatigue, decreased appetite, and hand-foot syndrome (HFS), were either mild or moderate and tolerable.

Since there is currently no effective treatment for patients with advanced NSCLC patients with brain metastasis who have already undergone two or more lines of treatment, the promising efficiency of apatinib combined with pemetrexed or docetaxel would be of great significance for these heavily ill patients. The real therapeutic value of this method against brain metastasis needs to be confirmed by large, random, and prospective clinical trials in the future.

The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment. Within this landscape, the innate immune system, a critical sentinel protecting against tumor incursion, is a key player. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway has been found to be a linchpin of innate immunity: activation of this signaling pathway orchestrates the production of type I interferon (IFN-α/β), thus fostering the maturation, differentiation, and mobilization of immune effectors in the tumor microenvironment. Furthermore, STING activation facilitates the release and presentation of tumor antigens, and therefore is an attractive target for cancer immunotherapy. Current strategies to activate the STING pathway, including use of pharmacological agonists, have made substantial advancements, particularly when combined with immune checkpoint inhibitors. These approaches have shown promise in preclinical and clinical settings, by enhancing patient survival rates. This review describes the evolving understanding of the cGAS-STING pathway's involvement in tumor biology and therapy. Moreover, this review explores classical and non-classical STING agonists, providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies. Despite challenges and complexities, the cGAS-STING pathway, a promising avenue for enhancing cancer treatment efficacy, has the potential to revolutionize patient outcomes.

The dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of chemotherapeutics and therapeutic antibodies, causing poor chemoimmunotherapy responses. We designed a multi-targeted pH-sensitive liposome which encapsulates cisplatin (Pt) in its water core (denoted as ATF@Pt Lps) and shows high affinity for uPAR receptors in pancreatic cancer cells, tumor-associated macrophages, and cancer-associated fibroblasts. Systemic administration of ATF@Pt Lps enabled overcoming the central stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in a Panc02 cell derived transplanted tumor mouse model. More importantly, ATF@Pt Lps degradation of collagen contributes to the infiltration of CD8+ T cells into tumors as well as an enhanced accumulation of anti PD-1 monoclonal antibodies. Furthermore, the killing of tumor cells by Pt also leads to the release of tumor antigens, which promote the proliferation of immune cells, especially CD83+ cells, Th1 CD4+ cells, and CD8+ cytotoxic T cells, that converted an immunoscore "cold" pancreatic cancer into a pro-immune "hot" tumor. A further combination with an immune checkpoint agent, anti PD-1 antibodies that inhibit PD-1, can enhance tumor specific cytotoxic T cell response. Accordingly, ATF@Pt Lps displays multi-targeting, controlled drug release, stromal disruption, enhanced penetration, killing of cancer cells, modification of the immunosuppressive microenvironment, and enhancement of immunity. This study provides important mechanistic information for the further development of a combination of ATF@Pt Lps and anti PD-1 antibodies for the effective treatment of pancreatic cancer.

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to access of toxicity. ONC201 targets DR5 to induce apoptosis in several types of cancers and has an excellent safety profile. ONC201 is also a dual PI3K/AKT and MEK pathways inhibitor. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable, which can be stabilized by prodrug approach. Here, we used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. We evaluated the efficacy of L_GEM and ONC201 in PanCan cells, and "KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. ONC201, in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade, to overcome chemoresistance, and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

Recent studies have expanded the known functions of cGAS-STING in inflammation to a role in cancer due to its participation in activating immune surveillance. In cancer cells, the cGAS-STING pathway can be activated by cytosolic dsDNA derived from genomic, mitochondrial and exogenous origins. The resulting immune-stimulatory factors from this cascade can either attenuate tumor growth or recruit immune cells for tumor clearance. Furthermore, STING-IRF3-induced type I interferon signaling can enforce tumor antigen presentation on dendritic cells and macrophages and thus cross-prime CD8+ T cells for antitumor immunity. Given the functions of the STING pathway in antitumor immunity, multiple strategies are being developed and tested with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells to elicit immunostimulatory effects, either alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. Based on the canonical molecular mechanism of STING activation, numerous strategies for inducing mitochondrial and nuclear dsDNA release have been used to activate the cGAS-STING signaling pathway. Other noncanonical strategies that activate cGAS-STING signaling, including the use of direct STING agonists and STING trafficking facilitation, also show promise in type I interferon release and antitumor immunity priming. Here, we review the key roles of the STING pathway in different steps of the cancer-immunity cycle and characterize the canonical and noncanonical mechanisms of cGAS-STING pathway activation to understand the potential of cGAS-STING agonists for cancer immunotherapy.

Triple-negative breast cancer (TNBC) is an aggressive molecular subtype that due to lack of druggable targets is treated with chemotherapy as standard of care. However, TNBC is prone to chemoresistance and associates with poor survival. The aim of this study was to explore the molecular mechanisms of chemoresistance in TNBC. Firstly, we found that the mRNA expression of Notch1 and CD73 in cisplatin-treated patient material associated with poor clinical outcome. Further, both were upregulated at the protein level in cisplatin-resistant TNBC cell lines. Overexpression of Notch1 intracellular domain (termed N1ICD) increased expression of CD73, whereas knockdown of Notch1 decreased CD73 expression. Using chromatin immunoprecipitation and Dual-Luciferase assay it was identified that N1ICD directly bound the CD73 promoter and activated transcription. Taken together, these findings suggest CD73 as a direct downstream target of Notch1, providing an additional layer to the mechanisms underlying Notch1-mediated cisplatin resistance in TNBC.

Exploring the regulation of co-inhibitory (PD-1, PD-L1, CTLA-4) and co-stimulatory (CD28) genes by chemotherapeutic drugs is important for combined immune checkpoint blockade (ICB) therapy. ICB interferes with T-cell receptor and major histocompatibility complex (MHC) signaling by antibody drugs directed against the co-inhibitors. Here, we analyzed urothelial (T24) cell line with respect to cytokine signaling by interferon γ (IFNG) and the leukemia lymphocyte (Jurkat) cell line with respect to T-cell activation as mimicked by phorbolester and calcium ionophore (pma/iono). Alongside, we considered possible intervention with the chemotherapeutics gemcitabine, cisplatin and vinflunine. Noteworthy, cisplatin significantly induced PD-L1-mRNA in naïve and IFNG treated cells whereas gemcitabine and vinflunine had no effect on PD-L1-mRNA. At the protein level, PD-L1 showed typical induction in IFNG treated cells. In Jurkat cells, cisplatin significantly induced PD-1-mRNA and PD-L1-mRNA. Pma/iono administration did not alter PD-1-mRNA and PD-L1-mRNA but significantly increased CTLA-4-mRNA and CD28-mRNA levels where vinflunine suppressed the CD28-mRNA induction. In sum, we demonstrated that certain cytostatic drugs being relevant for the therapy of urothelial cancer, affect co-inhibitory and co-stimulatory modulators of immune signaling with potential impact for perspective combined ICB therapy of patients. MHC-TCR signaling between antigen presenting cells and T-lymphocytes with co-stimulator (blue) and co-inhibitors (red) and interacting proteins (blank). Co-inhibitory connections are shown by lines and co-stimulatory connections by dotted lines. The inducible or suppressive actions of the drugs (underlined) on the respective targets are indicated.

Paclitaxel-based chemotherapy represented by nanoparticle albumin-bound paclitaxel (nab-ptx) combined with programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has become the standard model for the 1st treatment of advanced non-small cell lung cancer (NSCLC) with negative driver genes (such as EGFR, ALK, etc.), indicating that nab-ptx and PD-1/PD-L1 inhibitors are synergistic. Considering PD-1/PD-L1 inhibitors alone or chemotherapy single has limited efficiency in the 2nd line or above of NSCLC, so it is of great significance to explore the combination of PD-1/PD-L1 inhibitors and nab-ptx to further improve the therapeutic efficiency in such field.

We retrospectively collected the date of these advanced NSCLC patients who accept the combination treatment of PD-1/PD-L1 inhibitor and nab-ptx in the 2nd or above line. We further analysed baseline clinical characteristics, therapeutic efficacy, treatment-related adverse events (AEs) and followed up survival. The main parameters of the study were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs.

A total of 53 patients were enrolled in this study. The preliminary results indicated that the ORR of the combination of camrelizumab and nab-ptx was about 36% in the 2nd or above line of NSCLC, with 19 cases of partial response (PR), 16 of stable disease (SD), and 18 cases of progressive disease (PD); the mean PFS and OS were 5 months and 10 months, respectively. Further subgroup analysis demonstrated that the expression of PD-L1 level and the decrease of regulatory T cell (Treg) correlated with the efficiency. the main adverse reactions were neuropathy, bone marrow suppression, fatigue, and hypothyroidism, most of which were mild and tolerable, indicating such regimen was higher efficiency and lower cytotoxicity for NSCLC.

The combination of nab-ptx and camrelizumab shows promising efficiency and lower toxicities for advanced NSCLC in the 2nd or above line treatment. The mechanism of action may be related to depleting Treg ratio; such a regimen may have the potential to become an effective treatment approach for NSCLC. However, due to the limitation of sample size, the real value of this regimen needs to be further confirmed in the future.

The slightest change in the extra/intracellular concentration of metal ions results in amplified effects by signaling cascades that regulate both cell fate within the tumor microenvironment and immune status, which influences the network of antitumor immunity through various pathways. Based on the fact that metal ions influence the fate of cancer cells and participate in both innate and adaptive immunity, they are widely applied in antitumor therapy as immune modulators. Moreover, nanomedicine possesses the advantage of precise delivery and responsive release, which can perfectly remedy the drawbacks of metal ions, such as low target selectivity and systematic toxicity, thus providing an ideal platform for metal ion application in cancer treatment. Emerging evidence has shown that immunotherapy applied with nanometallic materials may significantly enhance therapeutic efficacy. Here, we focus on the physiopathology of metal ions in tumorigenesis and discuss several breakthroughs regarding the use of nanometallic materials in antitumor immunotherapeutics. These findings demonstrate the prominence of metal ion-based nanomedicine in cancer therapy and prophylaxis, providing many new ideas for basic immunity research and clinical application. Consequently, we provide innovative insights into the comprehensive understanding of the application of metal ions combined with nanomedicine in cancer immunotherapy in the past few years.

Immuno-checkpoint inhibitors (ICIs) bring a promising prospect for patients with cancers, which restrains the growth of tumor cells by enhancing anti-tumor activity. Nevertheless, not all patients benefit from the administration of ICIs monotherapy. The partial response or resistance to ICIs is mainly due to the complex and heterogenous tumor microenvironment (TME). The combined therapy is necessary for improving the efficacy of tumor treatment. Chemotherapy is reported not only to kill tumor cells directly, but also to stimulate effective anti-tumor immune responses. Several combined therapies of ICIs and chemotherapeutic agents have been approved for the first-line treatment of cancers, including PD-1/PD-L1 inhibitors. This review summarizes the potential mechanisms of the combined therapy of ICIs and chemotherapeutic agents in inducing immunogenic cell death (ICD) and reprogramming TME, and elucidates the possible anti-tumor effects of combined therapy from the perspective of metabolic reprogramming and microbiome reprogramming.

Oncogenic K-ras is often activated in pancreatic ductal adenocarcinoma (PDAC) due to frequent mutation (>90%), which drives multiple cellular processes, including alterations in lipid metabolism associated with a malignant phenotype. However, the role and mechanism of the altered lipid metabolism in K-ras-driven cancer remains poorly understood. In this study, using human pancreatic epithelial cells harboring inducible K-rasG12D (HPNE/K-rasG12D) and pancreatic cancer cell lines, we found that the expression of phospholipase A2 group IIA (PLA2G2A) was upregulated by oncogenic K-ras. The elevated expression of PLA2G2A was also observed in pancreatic cancer tissues and was correlated with poor survival of PDAC patients. Abrogation of PLA2G2A by siRNA or by pharmacological inhibition using tanshinone I significantly increased lipid peroxidation, reduced fatty acid synthase (FASN) expression, and impaired mitochondrial function manifested by a decrease in mitochondrial transmembrane potential and a reduction in ATP production, leading to the inhibition of cancer cell proliferation. Our study suggests that high expression of PLA2G2A induced by oncogenic K-ras promotes cancer cell survival, likely by reducing lipid peroxidation through its ability to facilitate the removal of polyunsaturated fatty acids from lipid membranes by enhancing the de novo fatty acid synthesis and energy metabolism to support cancer cell proliferation. As such, PLA2G2A might function as a downstream mediator of K-ras and could be a potential therapeutic target.