2026年 · 第04卷第03期

Cancer immunotherapy has emerged as a promising complement to traditional treatments such as radiotherapy and chemotherapy. Although conventional therapies remain central to cancer management, the potential of immunotherapy is increasingly recognized. Immune checkpoint therapy, a key strategy in tumor immunotherapy, has demonstrated significant efficacy against solid tumors. However, its clinical application is hindered by its limited response rate, necessitating efforts to optimize its effectiveness. Recent studies have highlighted the pivotal role of the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon gene (STING) pathway in immune checkpoint therapy. Manganese (Mn), an essential trace element, regulates the activity of CD8+ T and natural killer (NK) cells by modulating the cGAS-STING pathway. Furthermore, the combination of Mn with anti-programmed cell death protein 1 therapy has demonstrated promising antitumor effects. Mn also influences immunogenic cell death (ICD), further augmenting its potential as an adjunct to tumor immunotherapy. Despite a growing body of research on the role of Mn in modulating the cGAS-STING pathway and inducing ICD, comprehensive reviews that synthesize these findings and explore the potential of Mn in enhancing immune checkpoint therapy are still lacking. This review aimed to fill this gap by examining the immune mechanisms by which Mn enhances immune checkpoint therapy and its overall impact on tumor immunotherapy.

Hypoxia, a hallmark of the tumor microenvironment (TME), drives cancer progression through immune modulation, angiogenesis promotion, metabolic reprogramming, and uncontrolled cell proliferation. This review explores the diverse functions of hypoxia-inducible factor (HIF) signaling in cancer development and progression, providing a comprehensive overview of the molecular pathways. HIFs, particularly HIF-1α and HIF-2α, regulate several genes related to cancer hallmarks such as invasion, metabolic reprogramming, angiogenesis, and therapy resistance, thus mediating a significant portion of the hypoxic response. Oxygen-dependent hydroxylation of proline and asparagine residues in HIF-α subunits is a key regulator of their stability and transcriptional activity. Notably, this complex interaction is regulated by multiple signaling pathways, including the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. In cancer, HIF signaling affects several aspects of tumor cell biology that contribute to the cancerous characteristics, including angiogenesis induction through the upregulation of vascular endothelial growth factor (VEGF) expression, metabolic reprogramming through the enhancement of the Warburg effect, facilitation of cancer invasion and metastasis by driving epithelial-to-mesenchymal transition (EMT) and matrix remodeling patterns, and mediation of therapeutic resistance partly due to the effects on drug efflux pumps and DNA damage repair. Direct and indirect HIF inhibitors—including small molecules, peptidomimetics, antibodies, and proteolysis-targeting chimeras (PROTACs)—are under preclinical and clinical evaluation for their therapeutic efficacy. Preclinical and early clinical trials have demonstrated significant synergistic effects in inhibiting tumor development when HIF inhibition is combined with traditional therapies (chemotherapy or radiation) or immunotherapies, emphasizing major clinical implications and the potential for improving patient outcomes. Although challenges exist, particularly regarding drug resistance, further research to improve therapeutic efficacy and prolong survival for patients is warranted.

Marine-derived compounds have emerged as a promising frontier in cancer research owing their remarkable structural diversity and broad-spectrum bioactivities. The marine environment, harboring diverse organisms (e. g., sponges, algae, tunicates, mollusks, and marine microbes), is a prolific source of novel bioactive molecules with potent anticancer activities. Key classes of these compounds include alkaloids, polysaccharides, peptides, terpenoids, and polyketides, which exert antitumor effects through diverse mechanisms, including the induction of apoptosis, inhibition of angiogenesis, modulation of immune responses, interference with cell cycle progression, and targeting of critical signaling pathways involved in tumorigenesis and metastasis. Notably, marine-derived drugs such as trabectedin, eribulin, and plitidepsin have received regulatory approval for the treatment of various malignancies, demonstrating the translational potential of these natural compounds. Ongoing clinical and preclinical investigations are exploring a wide range of marine metabolites for their cytotoxic, antiproliferative, and chemosensitizing properties. Advances in marine biotechnology, including genome mining, synthetic biology, and fermentation technologies, have significantly facilitated the discovery, sustainable production, and structural optimization of marine natural products. However, challenges such as low yield, structural complexity, limited water solubility, and poor bioavailability hinder their broader clinical application. The integration of novel drug delivery systems, such as nanoparticles, liposomes, and conjugates, offers a viable solution to overcome these limitations and improve pharmacokinetic profiles. This review provides a comprehensive overview of the mechanisms of action, therapeutic applications, and clinical development of marine-derived anticancer compounds. It also emphasizes the need for deeper insights into their molecular targets and the potential for synergistic use with existing chemotherapeutic agents. Future directions should focus on exploring untapped marine biodiversity, developing eco-friendly harvesting strategies, and developing innovative delivery platforms to fully harness the therapeutic promise of the marine pharmacopeia in oncology.

Physiologically, the C-X-C chemokine receptor type 4 (CXCR4) signalling pathway regulates key aspects of tumor behavior (growth, metastasis, and immune evasion) and modulates immune system function. Anticancer researchers have identified peptide-based CXCR4 antagonists as promising candidates due to their high targeting specificity and favorable safety profiles. This review provides an analytical examination of CXCR4 antagonistic peptides, with a particular focus on mavorixafor (X4P-001), an advanced and highly selective CXCR4 inhibitor. By competing with C-X-C motif chemokine ligand 12 (CXCL12) for binding to CXCR4, Mavorixafor disrupts the receptor, inhibiting cancer-promoting signals, tumor spread, and angiogenesis. Mavorixafor blocks cancer cell progression and metastatic growth in different tumor models while enhancing chemotherapy, radiotherapy, and immune checkpoint inhibitor efficacy. Antagonistic peptides AMD3100 (Plerixafor), LY2510924, and POL6326, as well as their therapeutic potential. Mavorixafor is a promising option for cancer treatments that combine different therapies because it stays attached to its target for a long time and can be taken by mouth. Clinical studies have demonstrated that Mavorixafor produces promising outcomes when combined with chemotherapy or immune checkpoint inhibitors during the treatment of both hematological malignancies and solid tumors. Mavorixafor is promising for cancer treatment because it works well with other therapies, such as immune checkpoint inhibitors and chemotherapy, as well as targeted therapies and radiation therapy. Future research on Mavorixafor will focus on two main areas: personalized medicine development, new delivery systems and their broad medical applications extending beyond oncology. As a potential CXCR4 antagonist, Mavorixafor shows promise as a transformative tool in cancer care because it regulates the tumor microenvironment (TME) while increasing the degree of therapeutic benefits.

Background: Particle beam radiotherapy (PBRT), with its advantageous physical and biological properties, has the potential to improve therapeutic outcomes. To elucidate future clinical trial designs and policy decisions, we conducted this cross-sectional analysis of PBRT trials. Methods: We identified and analyzed the PBRT trials registered on ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform from September 27, 2007 to June 3, 2023, examining key characteristics and comparing completed trials with those terminated prematurely. Results: A total of 416 PBRT trials were identified, comprising 285 proton therapy trials and 131 carbon ion therapy trials. The number of PBRT trials increased steadily from 101 (2007-2012) to 172 (2017-2023) but declined sharply after 2021. Despite decades of development, more than 70.0% of PBRT trials remained in phase I/II, and more than 50% had sample sizes of fewer than 50 participants (carbon ion: 67.9%; proton: 49.5%). Compared with proton therapy trials, carbon ion trials tended to exclude elderly individuals more strictly (P < 0.001). Carbon ion trials were conducted predominantly in Asia (77.1%) and were more likely to receive government funding (22.1% vs. 7.7%, P < 0.001). Digestive system cancers and prostate cancer have been the primary indications for PBRT trials, although the proportion of head and neck tumors has been increasing annually. Moreover, early termination trials were more common among preregistered (P = 0.002), small sample-size (P < 0.001), elderly inclusive (P = 0.020), and nongovernment-funded (P = 0.003) clinical trials. Compared with PBRT, X-ray radiotherapy (XRT) features standardized trial designs and provides greater flexibility in terms of age limitations. Conclusion: Despite decades of development, clinical application of PBRT remains in the preliminary exploration stage. Our study provides a comprehensive overview of PBRT trials over the past fifteen years, may inform future trial designs and policy formulation.

Background: Ruxolitinib (RUX) impairs antiviral immunity in patients with hematologic malignancies. For steroid-refractory acute graft-versus-host disease (aGVHD), studies have yielded conflicting results regarding whether RUX treatment increases the risk of Epstein-Barr virus (EBV) infection. However, in newly diagnosed aGVHD, the use of RUX raises concerns about the potential risk of EBV infection. This study aimed to assess the incidence of EBV reactivation and EBV-related posttransplant lymphoproliferative disease (EBV-PTLD) in patients receiving a regimen of 5 mg/day RUX combined with 1 mg·kg-1·d-1 methylprednisolone as first-line therapy for aGVHD. Method: In this retrospective cohort study, allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients were consecutively screened at the Chinese PLA General Hospital. Patients who developed grade II-IV aGVHD were retrospectively categorized on the basis of first-line treatment. The RUX plus steroid (RUX-steroid) group (5 mg/day RUX + 1 mg·kg-1·d-1 methylprednisolone) included patients who received this dose in a phase 2 dose-escalation study of RUX, the intervention arm of a phase 3 trial evaluating this regimen as first-line therapy for aGVHD, and patients who were deemed unsuitable for high-dose steroids owing to active infections. The steroid regimen group (2 mg·kg-1·d-1 methylprednisolone) included patients treated in routine clinical practice and those in the control arm of the same phase 3 trial. EBV reactivation, EBV-PTLD incidence, and other transplantation outcomes were assessed. T-cell reconstitution was also analyzed at day 100 post-transplant. Results: A total of 487 patients treated between January 2018 and December 2023 were included in this study, with a median follow-up of 26.6 months (range, 2.8-69.9). Among these patients, 105 received RUX (5 mg/day) plus methylprednisolone (1 mg·kg-1·d-1) as a first-line treatment for grade II-IV aGVHD and were categorized into the RUX-steroid group. Moreover, 115 patients who received methylprednisolone alone (2 mg·kg-1·d-1) formed the steroid group. The median duration of RUX exposure was 177 days (range, 17-447 days). The cumulative incidence of EBV reactivation within 180 days was significantly greater in the RUX-steroid group (82.9%) than that in the steroid group (70.2%) (hazard ratio [HR]: 1.43, 95% CI: 1.03-1.97; P = 0.03). The cumulative incidence of PTLD was comparable between the RUX-steroid group (5.0%) and the steroid group (4.5%) (HR: 1.12, 95% CI: 0.33-3.83; P = 0.86). Multivariate analysis revealed that the use of a matched-sibling donor (MSD) was significantly associated with a decreased risk of both EBV reactivation (p < 0.001) and EBV-PTLD (P = 0.034). The 2-year nonrelapse mortality (NRM) was 14.9% in the RUX-steroid group, comparable to 13.7% in the steroid group (HR: 1.01, 95% CI: 0.50-2.03; P = 0.98). Conclusion: RUX was associated with an increased risk of EBV reactivation in patients after allo-HSCT but not with PTLD. Regular monitoring of the EBV viral load to enable timely intervention remains essential in these patients.

Background: Although chemotherapy combined with immunotherapy is effective in advanced non-small cell lung cancer (NSCLC), its efficacy in patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations remains unclear. Methods: This retrospective analysis included 66 patients: 28 received chemotherapy plus immunotherapy, and 38 received chemotherapy alone. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was safety. In eligible patients with measurable disease, tumor response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. PFS was defined as the time from the first day of therapy to disease progression or death from any cause. Results: The median progression-free survival (mPFS) was 10.5 months (95% confidence interval (CI): 7.03-16.63 months) in the chemotherapy plus immunotherapy group and 6.23 months (95% CI: 4.53-7.07 months) in the chemotherapy alone group. There was a significant difference in efficacy between the chemotherapy plus immunotherapy and chemotherapy-alone groups (p < 0.001). Among the 25 patients evaluated for tumor response in the chemotherapy plus immunotherapy group, 11 (44%) achieved a partial response (PR), 8 (32%) had stable disease (SD), and 6 (24%) had progressive disease (PD). The objective response rate (ORR) was 11 (44%). Adverse events (AEs) included gastrointestinal reactions and myelosuppression. There were no significant differences in terms of safety between the two treatment groups. Conclusions: First-line chemotherapy plus immunotherapy confers significantly longer PFS than chemotherapy alone in EGFR ex20ins-mutant NSCLC, with no increased toxicity.