Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

A retrospective study of 18 pediatric patients with high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated that a fixed low-dose combination of nivolumab and bendamustine achieved an 88% complete response rate, with 1-year progression-free survival (PFS) of 88.2% and overall survival (OS) of 94.4%.

The rapid development of immunotherapy has shown preliminary clinical efficacy and significant anti-tumor effects in some cancer patients. Although immunotherapy has been approved for breast cancer, some breast cancer patients still do not benefit from it due to issues such as immunotherapy insensitivity and resistance. Mass cytometry, as a mature single-cell proteomic analysis method, with its high-throughput capabilities, has been widely used in the analysis of tumor immune microenvironments and immune cell subpopulations. Using mass cytometry to analyze the immune microenvironment of breast cancer and explore new immunotherapy targets can help improve the current status of breast cancer immunotherapy and develop personalized treatment plans for more patients. This review surveys the recent advancements in analyzing the single-cell components of breast cancer using mass cytometry technology and reviews the immune microenvironment of breast cancer as well as potential targets for immunotherapy. These results provide new insights for the subsequent research of the immune microenvironment of breast cancer and targeted immunotherapy.

Hepatocellular carcinoma (HCC) is a common malignancy associated with high morbidity and mortality rates worldwide. To improve the prognosis of HCC, early diagnosis is crucial. However, to date, little is known about the role of natural killer cell-related genes (NKCRGs) in predicting the prognosis of hepatocellular carcinoma patients. In this study, we identified 24 differentially expressed NKCRGs in HCC specimens from the TCGA dataset, including 22 upregulated genes and 2 downregulated genes. Functional enrichment analysis revealed that these genes were mainly involved in immune response pathways and various cancer-related pathways. Univariate analysis identified 21 prognostic NKCRGs, with eight genes (PAK1, MAP2K2, MAPK3, PLCG1, SHC1, HRAS, NRAS, and MICB) confirmed to be involved in HCC prognosis through Venn diagram analysis. A prognostic model was developed using LASSO-Cox regression, incorporating four genes (MAP2K2, SHC1, HRAS, and NRAS). The model's risk score was significantly associated with overall survival (OS) in both the TCGA and ICGC cohorts. Patients with high-risk scores had poorer OS, as demonstrated by Kaplan-Meier curves and ROC analyses. The risk score was not significantly correlated with gender or age but was higher in patients with advanced tumor grades and stages. Immune status analysis using ssGSEA showed higher enrichment scores for various immune cells and pathways in the high-risk group. Additionally, the risk score was positively correlated with the immune score, indicating its potential role in tumor microenvironment modulation. Expression analysis revealed that HRAS, SHC1, MAP2K2, and NRAS were upregulated in HCC tissues, with higher expressions of HRAS, MAP2K2, and NRAS associated with shorter OS. Knockdown experiments confirmed that silencing NRAS suppressed the proliferation of HCC cells, highlighting its potential as a therapeutic target. Overall, our findings suggest that the identified NKCRGs, particularly NRAS, play crucial roles in HCC progression and could serve as valuable prognostic markers and therapeutic targets.

Lung cancer remains a significant global health challenge, demanding innovative treatment strategies. Immune checkpoint blockade has revolutionized cancer care, leading to improved survival across advanced malignancies and has now become a standard therapy for earlier stage, resectable lung cancer. This review article consolidates the current landscape and future prospects of neoadjuvant and perioperative immunotherapy in lung cancer. The authors outline key findings from clinical trials in resectable lung cancer, including early efficacy, safety profiles, and emerging impact on disease recurrence, and overall survival. Additionally, this review elucidates the challenges encountered, including patient selection criteria, optimal treatment schedules, immune-related adverse events, and impact on surgery. This comprehensive analysis amalgamates current evidence with future directions, providing a roadmap for clinicians, researchers, and stakeholders to navigate the dynamic realm of immunotherapy for surgically resectable lung cancer.

Penile cancer considered an orphan malignancy - due to its low incidence - makes research and clinical development challenging. The limited understanding of molecular biology and genetic landscape adds to the complexity of developing effective therapies.

This review takes a closer look at how penile cancer treatment has evolved - from traditional modes like surgery and radiation to now vaccines - over the period of time. Breakthroughs in immunotherapy offer a ray of hope alongside treatments like adoptive T-cell therapies (ATCT), anti-angiogenic agents, Antibody-Drug Conjugates (ADCs), and Bispecific Antibodies (BsAbs).

The integration of immunotherapy and targeted therapy has demonstrated promising results, particularly in patients with advanced or metastatic disease. While these advancements bring hope, more research is needed to refine treatment strategies to benefit patients from these novel approaches.

Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.

Treatment strategies that enhance the efficacy of immunotherapy are desired. Radiotherapy can enhance immunity, but the utility of adding radiotherapy to immunotherapy plus platinum-doubled chemotherapy in patients with metastatic NSCLC has not been explored.

This multicenter, single-arm phase 2 trial evaluated the efficacy and safety of combining radiotherapy with pembrolizumab plus chemotherapy in patients with previously untreated metastatic NSCLC. Patients begin receiving pembrolizumab plus platinum-doublet chemotherapy within 1 week of starting radiotherapy (30 Gy in 10 fractions). The primary end point was the 12-month progression-free survival (PFS) rate. The secondary end points included PFS, overall survival, and toxicity profiles.

Forty patients were enrolled. In total, 37 and 38 patients were analyzed for efficacy and safety, respectively. The 12-month PFS rate was 44.3% (90% confidence interval [CI]: 30.3-57.3), which met the primary end point. The median PFS was 8.4 months (95% CI: 5.7-22.2), and the median overall survival was 30.1 months (95% CI: 22.3-not reached). Grade 3 or 4 adverse events occurred in 25 patients (65.8%), and one treatment-related death was reported. Pneumonitis was reported in 10 patients (26.3%), including two cases of grade 3 pneumonitis and one case of grade 5.

Adding radiotherapy to pembrolizumab plus platinum-doublet chemotherapy led to promising efficacy in patients with previously untreated metastatic NSCLC. Although caution should be exercised with regard to pneumonitis, adverse events were tolerable. Further research is needed to confirm the efficacy and safety of this strategy.

Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepatocellular carcinoma (HCC) patients' response to immune checkpoint inhibitors (ICIs). We categorized HCC patients into various immune subtypes based on feature scores linked to ICI response. Single-cell sequencing technology was to investigate the cellular heterogeneity of different immune subtypes and acquire significant ICI response-associated cells. Candidate drugs were identified using a blend of various drug databases and network approaches. HCC patients were divided into two distinct immune subtypes based on characterization scores of 151 immune-related gene sets. Patients in both subtypes showed varying overall survival, immunity levels, biological activities, and TP53 mutation rates. Subtype 1-related natural killer cells showed a positive correlation with immune-promoting scores but a negative correlation with immune-suppressing scores. Notably, docetaxel sensitivity in HCC patients rose as the levels of subtype 1-related natural killer cells increased. Our study demonstrated that immune subtypes have cellular heterogeneity in predicting response to ICIs. A combination of subtype 1-associated natural killer cells and docetaxel may offer new hope for ICI treatment in HCC.

Conventional chemotherapeutic agents, such as 5-fluorouracil (5-FU), can exert anti-tumor effects through immunogenic cell death (ICD) induction. Researchers have found hallmarks that quantify ICD (such as the translocation of HMGB1 and calreticulin). Although chemotherapeutic agents can induce ICD, they increase the expression of immune checkpoints, limiting their effectiveness. Studies have emphasized the importance of investigating the heterogeneous responses of cells co-localized in a solid tumor (macrophages, tumor cells, etc.) to ICD induction. However, these studies were performed in vivo, which limits the collection of information on cell-cell interactions due to model complexity.

In this study, we used a multicellular spheroid model in conjunction with single spheroid imaging to understand the structural and metabolic changes of a simulated solid tumor model. In addition to using the spheroid model, conventional 2D co-culture monolayers were used to quantify ICD hallmarks and changes in macrophage functional behavior while correlating immune responses after exposure to the combinatory regimen of immune checkpoint inhibitors and an ICD inducer.

Results indicate that the combination of two immune checkpoint inhibitors in addition to a chemotherapy agent reduced spheroid growth (~46%) and reduced M2 macrophage expression and cellular proliferation while modulating cellular metabolism, ICD hallmarks, and phagocytic function.

Overall, this study not only quantified microregional metabolic and structural changes in a simulated spheroid model but also quantified changes in ICD hallmarks and macrophage functional behavior. It was also found that correlations between spheroid structure and ICD hallmarks through immunofluorescence markers could exist after exposure to the combinatory regimen of immune checkpoint inhibitors and an ICD inducer.

In cancer therapy, enhancing therapeutic indices and patient compliance has been a central focus in recent drug delivery technology development. However, achieving a delicate balance between improving anti-tumor efficacy and minimizing toxicity to normal tissues remains a significant challenge. With the advent of smart on-demand drug release strategies, new opportunities have emerged. These strategies represent a promising approach to drug delivery, enabling precise control over the release of therapeutic agents in a programmed and spatiotemporal manner. Recent studies have focused on designing delivery systems capable of releasing multiple therapeutic agents sequentially, while achieving spatial resolution in vivo. Smart on-demand drug release strategies have demonstrated considerable potential in tumor combination therapy for achieving precision drug delivery and controlled release by responding to specific physiological signals or external physical stimuli in the tumor microenvironment. These strategies not only improve tumor targeting and reduce toxicity to healthy tissues but also enable sequential release in combination therapy, allowing multiple drugs to be released in a specific spatiotemporal order to enhance synergistic treatment effects. In this paper, we systematically reviewed the current research progress of smart on-demand drug release drug delivery strategies in anti-tumor combination therapy. We highlighted representative integrated drug delivery systems and discussed the challenges associated with their clinical application. Additionally, potential future research directions are proposed to further advance this promising field.

Immunochemotherapy combinations have been the standard first-line therapy for advanced lung adenocarcinoma (LUAD) without driver mutations, wherein concurrent chemotherapy and immunotherapy are conventionally anchored in the established dosing regimen. A few studies have suggested that the timing of immunotherapy in combinations may have a significant impact on the efficacy. However, this issue has not been addressed in an advanced LUAD cohort. We aimed to investigate the prognostic significance of the timing of immunotherapy in first-line immunochemotherapy combinations for patients with advanced LUAD. We retrospectively analyzed 508 patients with advanced LUAD without driver mutations who received immunochemotherapy as initial systemic treatment. The patients were divided into two groups-the induction and non-induction groups-with induction defined as receiving chemotherapy alone before concurrent immunochemotherapy. The bias between different groups was minimized using propensity score matching (PSM). We found both the PFS and OS of the patients in the induction group were significantly longer than those in the non-induction group before (PFS: p < 0.0001, OS: p < 0.0001) and after PSM (PFS: p = 0.0045, OS: p = 0.00073). After adjusting for confounders, induction chemotherapy was still a significant favorable factor for both PFS (p = 0.001) and OS (p = 0.001). In subsequent analyses, we found that both ≥2-cycles induction (PFS: p = 0.000, OS: p = 0.000) and 1-cycle induction (PFS: p = 0.013, OS: p = 0.002) were superior to non-induction and these differences were still significant after PSM. Our findings highlight the notable benefits of induction chemotherapy for patients with advanced LUAD treated with first-line immunochemotherapy combinations.

Non-small cell lung cancer (NSCLC) continues to be one of the leading causes of cancer-related mortality globally. Most patients who undergo surgical procedures may encounter distant metastasis or local recurrence, necessitating supplementary treatments such as radiation therapy, chemotherapy, or targeted therapy as adjuvant alternatives. Recent advancements in molecular biology and immunotherapy have paved the way for innovative therapeutic approaches that target specific genetic mutations and promote the immune response against tumour cells. This review explores emerging therapies, including targeted therapies such as tyrosine kinase inhibitors (TKIs) for actionable mutations (e.g., EGFR, ALK, ROS1), as well as the role of immune checkpoint inhibitors (ICIs) that employ the body's immune system to combat cancer. Additionally, we discuss the potential of exosome therapies, as well as promising nanotherapeutic options for the treatment of NSCLC. This study attempts to provide a thorough overview of the changing landscape of NSCLC treatment and its implications for enhancing patient outcomes by presenting these innovative techniques.

The abnormal tumor mechanical microenvironment due to specific cancer-associated fibroblasts (CAFs) subset and low tumor immunogenicity caused by inefficient conversion of active chemotherapeutic agents are two key obstacles that impede patients with desmoplastic tumors from achieving stable and complete immune responses. Herein, it is demonstrated that FAP-α+CAFs-induced stromal stiffness accelerated tumor progression by precluding cytotoxic T lymphocytes. Subsequently, a cascade-responsive nanoprodrug capable of re-educating FAP-α+CAFs and amplifying tumor immunogenicity for potentiated cancer mechanoimmunotherapy is ingeniously designed. Benefiting from the active targeted release of angiotensin II receptor antagonist (losartan) guided by FAP-α cleavable peptide and the efficient conversion of topoisomerase I inhibitor (7-Ethyl-10-hydroxycamptothecin) prodrug under high glutathione/esterase within tumor cells, this regimen created an immune-activated landscape that retarded primary tumor growth and counteracted resistance to immune checkpoint inhibitor in mice with triple-negative breast cancer. This nanoprodrug-assisted mechanoimmunotherapy can serve as a universal strategy for conferring efficient tumoricidal immunity in "immune excluded" desmoplastic tumor interventions.

Pembrolizumab, a PD-1 inhibitor, has shown potential for treating advanced gastric and gastroesophageal junction (GEJ) cancer. This meta-analysis evaluates its efficacy and safety, alone or combined with chemotherapy, in this population.

A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. Databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched up to October 31, 2024. Twelve studies comprising 4,069 patients were included. The primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate (ORR), adverse events (AEs), and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MDs) and odds ratios (ORs) with 95% confidence intervals (CIs).

Pembrolizumab combined with chemotherapy significantly improved OS (MD = 1.92 months; 95% CI: 0.94 to 2.91) and ORR (MD = 11.05%; 95% CI: 6.29 to 15.82) compared to chemotherapy alone. Pembrolizumab monotherapy did not show a significant effect on OS (MD = 0.24 months; 95% CI: -1.15 to 1.63) and was associated with a significant reduction in PFS (MD = -2.28 months; 95% CI: -2.85 to -1.71) compared to chemotherapy alone. For safety, pembrolizumab monotherapy significantly reduced the risk of AEs (OR = 0.68; 95% CI: 0.57 to 0.81) and grade ≥ 3 AEs (OR = 0.39; 95% CI: 0.30 to 0.51) compared to chemotherapy. Pembrolizumab combined with chemotherapy did not significantly alter the risk of AEs (OR = 1.01; 95% CI: 0.90 to 1.13) or grade ≥ 3 AEs (OR = 1.12; 95% CI: 0.99 to 1.27) compared to chemotherapy alone.

Pembrolizumab combined with chemotherapy improves survival and response rates with a manageable safety profile in advanced gastric and GEJ cancers. Monotherapy shows limited efficacy, highlighting the need for combination strategies and patient selection.

In this study, we aimed to develop a predictive model for patients receiving chemotherapy and immunotherapy for extensive-stage small cell lung cancer.

We retrospectively analyzed 112 extensive-stage small cell lung cancer patients treated with first-line immunotherapy and chemotherapy. The relevant clinical data were collected to evaluate the changes during the treatment. The best subset regression, univariate analysis, and LASSO regression with cross-validation were applied for variable selection and model establishment. The nomograms for 1- and 2-year survival probabilities were established, and the calibration curve was utilized to evaluate the correspondence between actual and predicted survival. The model prediction capacity was assessed using decision curve analysis, calibration curves, and receiver operating characteristic curves. Moreover, five-fold cross-validation was conducted for internal validation. According to risk score, the patients were assigned to high- and low-risk groups, and survival curves were generated for each group.

The LASSO regression model was established based on the variables such as age, ECOG, metastatic sites, NLR, and immunotherapy cycles. This predictive model displayed robust performance, evidenced by the Area Under the Curve of 0.887 and concordance index of 0.759. The nomogram effectively predicted 1- and 2-year survival probabilities and demonstrated a high degree of calibration. The decision curve analysis displayed that the model possessed superior predictive capability. The risk stratification for patients with high- and low-risk categories facilitated more individualized survival assessment.

The study successfully developed a prognostic model for extensive-stage small cell lung cancer patients undergoing immunotherapy and chemotherapy, demonstrating the good accuracy and predictability.

Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.

Immunotherapy options for microsatellite stable (MSS) colorectal cancer are currently very limited. The lack of detectably unique or altered immunogens in the tumor microenvironment may be a factor. Radiation and chemotherapy may enhance immunotherapy by increasing cancer cell visibility through Major Histocompatibility Complex I (MHC I) expression. To investigate this, we treated MSS and microsatellite-instable (MSI) colon cancer cells with a topoisomerase inhibitor and analyzed MHC I-associated peptides. Treatment increased peptide numbers by 5% in RKO (MSI) cells and 83% in SW620 (MSS) cells, with 40-50% of peptides being exclusive to treatment. Additionally, clustering analysis revealed a set of peptides with uniquely conserved residues displayed only in treated MSS SW620 cells. Gene Ontology analysis of MHC I-displayed proteins revealed a treatment-induced increase in extracellular vesicle- and nuclear-derived proteins, alongside reduced cytosolic protein sampling. Overall, we present evidence for treatment-inducible differential display of peptides, some of which may affect interactions and functions of immune cells. Given the multitude of factors that modulate the effects of increased MHC I expression and associated peptides, further studies are needed to elucidate the pathophysiological implications of these changes.

The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.

PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846).

This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5 mg/kg) and nab-paclitaxel (260 mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival.

Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached).

Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.

Chimeric antigen receptor (CAR) T-cell therapy has achieved potent antitumor efficacy in hematological malignancies; however, because of limitations in CAR T-cell recruitment, infiltration, activation, and functional persistence in the tumor, its efficacy in solid tumors has been suboptimal. To overcome these challenges, combinational strategies that include chemotherapy, radiation therapy, or immune checkpoint inhibitor agent therapy with CAR T-cell therapy are being investigated. The established functional characteristics of the abovementioned therapies provide a rationale for the use of a combinational approach with CAR T cells. Chemotherapy reshapes the peritumoral stroma, decreases the immunosuppressive cell population, and promotes a proinflammatory milieu, all of which allow for increased recruitment, infiltration, and accumulation of CAR T cells. Radiation therapy promotes a chemokine gradient, which augments tumor infiltration by CAR T cells and further increases expression of tumor-associated antigens, allowing for increased activation of CAR T cells. Immune checkpoint inhibitor agent therapy inactivates T-cell exhaustion pathways-most notably, the PD1/PDL1 pathway-thereby improving the functional persistence of CAR T cells and promoting endogenous immunity. In this review, we discuss the requisites and rationales for combinational therapy, and we review 25 ongoing phase I and II clinical trials, of which 4 use chemotherapy, 3 use radiation therapy, 11 use immunotherapy, and 7 use another agent. While safety, efficacy, and improved outcomes are the primary goals of these ongoing studies, the knowledge gained from them will help pave the way for subsequent studies focused on optimizing combinational regimens and identifying predictive biomarkers.

Immune checkpoint inhibitors (ICIs), which offer previously unknown therapeutic advantages, have revolutionized cancer treatment. However, the risk of thromboembolic events (TEEs) associated with ICIs remains unclear. The aim of this network meta-analysis (NMA) was to evaluate the incidence of TEEs in cancer patients receiving different treatment regimens.

We searched for randomized clinical trials (RCTs) between January 2021 and December 2023 without restricting the cancer type. The percentages of TEEs were systematically extracted. An NMA was performed comparing atezolizumab, cemiplimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, conventional therapy (which consists mainly of chemotherapy, targeted therapy, placebo, and their combinations), two ICI drugs, one ICI drug combined with conventional therapy, and two ICI drugs combined with conventional therapy. Additionally, subgroup analysis was conducted based on cancer type.

Eighty-three RCTs involving 54,736 patients were included. Patients receiving ICIs demonstrated comparable risks of arterial thromboembolism (ATE), deep vein thrombosis (DVT), myocardial infarction (MI), and cerebrovascular accidents (CVAs). Nivolumab (OR 0.39, 95 % CI 0.19 to 0.80) and two ICI drugs (OR 0.52, 95 % CI 0.29 to 0.89) had the lowest risk of venous thromboembolism (VTE) compared to two ICI drugs with conventional therapy. The risk of pulmonary embolism (PE) was greater for ipilimumab (OR 4.09, 95 % CI 1.13 to 15.51) than for nivolumab. For melanoma in the subgroup analysis, nivolumab significantly reduced the risk of VTE (OR 0.07, 95 % CI 0.00 to 0.76) compared to two ICI drugs. Among the single-ICI regimens, durvalumab was associated with the highest incidence of ATE, MI, and CVAs; ipilimumab had the highest incidence of VTE and PE; and pembrolizumab had the highest incidence of DVT. The combination of one ICI drug with conventional therapy was associated with a significantly greater risk of TEEs (except for MI) than the combination of two ICI drugs.

Various ICI regimens in cancer patients exhibit clinically significant differences in the risks of TEEs. Nivolumab exhibited a favorable safety profile regarding VTE, while ipilimumab had the highest risk of both VTE and PE. Different ICI regimens require tailored risk management strategies to reduce TEEs.

Immune checkpoint inhibitors (ICIs) are currently the primary approach for managing NSCLC. However, numerous combination therapies are currently under investigation. Our goal is to investigate the overall efficacy and safety of ICIs and taxane-based chemotherapy.

We conducted a systematic review and meta-analysis, searching web databases for relevant literature. We limited our eligibility to phase II/III randomized clinical trials involving advanced/metastatic NSCLC patients.

We performed a meta-analysis encompassing nineteen studies derived from sixteen RCTs. For patients with sq-NSCLC PD-L1 ≥ 50%, using ICIs plus taxane significantly improve PFS and OS with HR of 0.58 (95% CI, 0.45-0.74, p < 0.0001) and 0.41 (95% CI, 0.33-0.50, p < 0.00001), respectively. For patients with non-sq NSCLC PD-L1 1-49%, the analysis revealed significant improvement of OS and PFS with HR of 0.64 (95% CI, 0.47-0.88, p = 0.005) and 0.62 (95% CI, 0.47-0.81, p = 0.0004), respectively. For TRAEs of all grades, ICIs plus taxane resulted with no significant difference compared to control group with risk ratio (RR) 1.00 (95% CI 0.99-1.02).

The analysis revealed significant improvement in efficacy of ICIs with taxane in advanced/metastatic NSCLC patients compared with ICI/taxane monotherapy.Registration: PROSPERO (CRD42023447532).

Previously, we demonstrated that natural host-defence peptide caerin 1.1/caerin 1.9 (F1/F3) increases the efficacy of anti-PD-1 and therapeutic vaccine, in a HPV16 + TC-1 tumour model, but the anti-tumor mechanism of F1/F3 is still unclear. In this study, we explored the impact of F1/F3 on the tumor microenvironment in a transplanted B16 melanoma model, and further investigated the mechanism of action of F1/F3 using monoclonal antibodies to deplete relevant cells, gene knockout mice and flow cytometry. We show that F1/F3 is able to inhibit the growth of melanoma B16 tumour cells both in vitro and in vivo. Depletion of macrophages, blockade of IFNα receptor, and Stat1 inhibition each abolishes F1/F3-mediated antitumor responses. Subsequent analysis reveals that F1/F3 increases the tumour infiltration of inflammatory macrophages, upregulates the level of IFNα receptor, and promotes the secretion of IFNα by macrophages. Interestingly, F1/F3 upregulates CD47 level on tumour cells; and blocking CD47 increases F1/F3-mediated antitumor responses. Furthermore, F1/F3 intratumor injection, CD47 blockade, and therapeutic vaccination significantly increases the survival time of B16 tumour-bearing mice. These results indicate that F1/F3 may be effective to improve the efficacy of ICB and therapeutic vaccine-based immunotherapy for human epithelial cancers and warrants consideration for clinical trials.

The excision of introns from pre-mRNA is a crucial process in the expression of the majority of genes. Alternative splicing allows a single gene to generate diverse mRNA and protein products. Aberrant RNA splicing is recognized as a molecular characteristic present in almost all types of tumors. Therefore, identifying cancer-specific subtypes from aberrant processing offers new opportunities for therapeutic development. Numerous splicing modulators, each utilizing different mechanisms, have been developed as promising anticancer therapies, some of which are in clinical trials. In this review, we summarize the splice-altered signatures of cancer cell transcriptomes and the contributions of splicing aberrations to tumorigenesis and progression. Especially, we discuss current and emerging RNA splicing-targeted strategies for cancer therapy, including pharmacological approaches and splice-switching antisense oligonucleotides (ASOs). Finally, we address the challenges and opportunities in translating these findings into clinical practice.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

The advent of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) treatment marks a major breakthrough. These therapies have proven safer and more effective than traditional radiotherapy and targeted treatments. Immunotherapies like pembrolizumab, nivolumab, and ipilimumab have pioneered new treatment avenues, potentially improving patient outcomes and quality of life. Additionally, advances in immunotherapy have prompted detailed research into CRC therapies, especially those integrating ICIs with conventional treatments, providing new hope for patients and shaping future research and practice. This review delves into the mechanisms of various ICIs and evaluates their therapeutic potential when combined with radiotherapy, chemotherapy, and targeted therapies in clinical settings. It also sheds light on the current application and research involving ICIs in CRC treatment.

Drugs represent our first, and sometimes last, line of defense for many diseases, yet despite decades of research we still do not fully understand why a given drug works in one patient and fails in the next. The human gut microbiome is one of the missing puzzle pieces, due to its ability to parallel and extend host pathways for drug metabolism, along with more complex host-microbiome interactions. Herein, we focus on the well-established links between the gut microbiome and drugs for heart disease and cancer, plus emerging data on neurological disease. We highlight the interdisciplinary methods that are available and how they can be used to address major remaining knowledge gaps, including the consequences of microbial drug metabolism for treatment outcomes. Continued progress in this area promises fundamental biological insights into humans and their associated microbial communities and strategies for leveraging the microbiome to improve the practice of medicine.

Gastric cancer, as the fifth most diagnosed malignancy and the fourth leading cause of cancer-related death globally, remains a significant health concern. The potential effect of the programmed death-1 (PD-1) inhibitor, when used alongside chemotherapy and antiangiogenic agents in neoadjuvant therapy for gastric cancer, has yet to be explored in the published literature. This study aims to evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen when combined with apatinib and camrelizumab (SOXAC) as neoadjuvant therapy for patients with locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. A single-arm, open-label, single-center phase II clinical trial has been designed to evaluate the safety and efficacy of the SOXAC regimen as neoadjuvant therapy for patients diagnosed with locally advanced gastric or GEJ adenocarcinoma (cT2-3N + M0 or T4NxM0). Eligible patients are to receive 2 cycles of SOXAC and 1 cycle of SOX regimen with camrelizumab (SOXC) as neoadjuvant therapy prior to radical surgery, and 3 cycles of SOXC as postoperative adjuvant therapy. The primary endpoint is major pathological remission (MPR), while secondary endpoints include pathological complete response (pCR) rate, R0 resection rate, objective response rate (ORR), operation-related outcomes, and safety. The SOX regimen remains a leading choice for neoadjuvant chemotherapy in Eastern countries. Recent studies suggest that combining chemotherapy, targeted agents, and immune checkpoint inhibitors can enhance the antitumor immune response. This phase II clinical trial seeks to assess the safety and efficacy of the SOXAC regimen as neoadjuvant therapy for patients with locally advanced resectable gastric or GEJ adenocarcinoma, while also exploring the correlation between biomarkers and efficacy.Trial Registration Chinese Clinical Trial Registry (ChiCTR): ChiCTR2200062285 ( https://www.chictr.org.cn/ ).

Immune checkpoint inhibitors (ICIs) combined with standard therapy (ST) have emerged as a novel treatment strategy for recurrent or advanced cervical cancer (r/a CC). However, the available data from phase 3 clinical trials have yielded mixed results. This study aims to evaluate the therapeutic efficacy and safety of adding ICIs to ST in the treatment of r/a CC.

Data from four phase 3 clinical trials (KEYNOTE-826, CALLA, BEATcc, and ENGOT-cx11/GOG-3047/KEYNOTE-A18), involving 2,857 patients, were analyzed. Meta-analyses were conducted to combine hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) for the objective response rate (ORR), and relative risks (RRs) for adverse events (AEs).

The addition of ICIs to ST significantly improved PFS (HR, 0.67; 95% CI, 0.60-0.75), OS (HR, 0.66; 95% CI, 0.58-0.75), and ORR (OR, 1.48; 95% CI, 1.13-1.94) compared to ST alone. However, there was a modest increase in grade 3-5 AEs (RR, 1.08; 95% CI, 1.03-1.13) with the combined therapy.

This meta-analysis indicates that the combination of ICIs with ST in the treatment of r/a CC not only demonstrates superior efficacy over ST alone but also maintains a comparable toxicity profile, offering strong evidence for an effective and relatively safe treatment approach for managing this disease.

https://www.crd.york.ac.uk/prospero/, identifier CRD42024593895.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for resectable non-small cell lung cancer. Numerous trials have explored the use of ICIs, either as monotherapy or in combination with other therapies, in the neoadjuvant setting for stage I-III non-small cell lung cancer. Most trials have demonstrated neoadjuvant immunotherapy to be safe and to have remarkable efficacy, with a high pathological response rate and significantly improved event-free survival. This review summarizes the findings of Phase I-III clinical trials investigating various neoadjuvant regimens, including ICI monotherapy, ICI therapy combined with chemotherapy, ICI plus anti-angiogenic therapy, dual ICI therapy, and ICI therapy in combination with radiotherapy or chemoradiotherapy. We discuss the benefits and outcomes associated with each approach. Despite the results being promising, several unresolved issues remain, including identification of reliable biomarkers, the appropriate duration of therapy, the optimal treatment regimen for tumors with high programmed cell death ligand 1 (PD-L1) expression, the false-negative pathological complete response rate, and the role of digital pathology in assessing the response to treatment. Resistance to immunotherapy, in particular, remains a significant barrier to effective use of ICIs. Given the critical influence of the tumor microenvironment (TME) on the response to treatment, we examine the characteristics of the TME in both responsive and resistant tumors as well as the dynamic changes that occur in the TME in response to neoadjuvant immunotherapy. We also summarize the mechanisms underlying T cell responses following neoadjuvant immunotherapy and provide a perspective on strategies to enhance the understanding of tumor heterogeneity, therapy-driven TME remodeling, and overcoming resistance to therapy. Finally, we propose future directions for advancements in personalized neoadjuvant immunotherapy.

Immunophenotypic analysis identified a BM CD57+CXCR3+ subset of CD8+ T cells associated with response to AZA in patients with MDS and AML. Single-cell RNA sequencing analysis revealed that IFN signaling is linked to the response to treatment, whereas TGF-β signaling is associated with treatment failure, providing insights into new therapeutic approaches.

Anti-PD-1/PD-L1 plus chemotherapy (CT) is considered the standard of care in first line treatment of metastatic NSCLC. However, the clinical benefit of this combination in older patients is controversial. We performed a meta-analysis of phase III randomized trials that compared PD-1/PD-L1 inhibitor plus CT with CT alone in first line of treatment for older patients with advanced NSCLC. Subgroups of patients over 65 and over 75 were analyzed. The outcomes included overall survival (OS) and progression-free survival (PFS). A fixedeffect model was used. We analyzed ten trials with an anti-PD-1 (camrelizumab, cemiplimab, nivolumab, pembrolizumab, tislelizumab or toripalimab) and six trials with an anti-PD-L1 (atezolizumab, durvalumab or sugemalimab), including 3666 patients over the age of 65 (41%) and 282 patients over the age of 75 (<10%). For patients over 65 years of age, anti-PD- 1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.79 [0.72-0.86]; p < 0.00001) and P FS (0.63 [0.58-0.68]; p < 0.00001) compared to CT alone. Survival benefits occurred in both anti-PD-1 and anti-PD-L1 trials. For patients over 75 years of age, OS benefit was not statistically significant (0.88 [0.67-1.16]; p = 0.37). For patients over the age of 65 with untreated NSCLC, the anti-PD-1/PD-L1 combination with CT, compared with CT alone, is associated with significantly improved OS and PFS. Due to the low number of patients, it is difficult to conclude for those over 75.

There are currently limited real-world data on the effectiveness and safety of first-line pembrolizumab combined with chemotherapy in patients with advanced/recurrent or metastatic esophageal squamous cell carcinoma (ESCC) in China. This study was conducted to address this knowledge gap.

This multicenter retrospective cohort study was conducted at 17 hospitals in China and included adults (⩾18 years) with stage IV primary ESCC, or recurring 6 months after radical radiotherapy/surgery-based combination therapy, who had received first-line pembrolizumab plus chemotherapy. Data were collected from electronic medical records. Endpoints included objective response rate (ORR), disease control rate (DCR) progression-free survival (PFS), overall survival (OS), and safety. Subgroup analyses were conducted to identify patient characteristics and treatment patterns associated with treatment response.

In total, 202 patients who had received treatment from 2018 to 2023 were included: 125 (61.9%) newly diagnosed and 77 (38.1%) with recurrence, 181 (89.1%) were male. Pembrolizumab was most commonly combined with paclitaxel + platinum (69.8%) or fluorouracil + platinum (19.3%). After a median follow-up of 22.6 months (95% confidence interval (CI) 20.1-25.4), the ORR and DCR were 60.9% and 87.6% and the median PFS and OS were 10.8 months (95% CI 9.1-13.5) and 17.3 months (95% CI 14.9-19.9), respectively. OS was similar in patients with treatment-naïve and recurrent disease. Among the combination chemotherapy regimens, paclitaxel + platinum was associated with the longest median OS (18.2 months, 95% CI 16.1-22.5). Favorable survival outcomes were observed in patients with oligometastases. No new safety signals were observed.

These real-world data indicate that the first-line treatment with pembrolizumab plus chemotherapy is effective and safe in Chinese patients with advanced ESCC and show that paclitaxel + platinum is the most commonly used and most effective partner chemotherapy in China.