Cancer letters最新文献

MSR1⁺ tumor-associated macrophages (TAMs) have been implicated in various malignancies; however, their functional role in Hepatocellular carcinoma (HCC) remains poorly defined. This research seeks to clarify the roles of MSR1⁺ TAMs in HCC and their influence on the tumor immune microenvironment. Clinical and experimental data indicate that high levels of MSR1⁺ TAMs correlate with poor prognosis in HCC patients. Transcriptomic analyses and in vitro as well as in vivo functional assays revealed that the immunosuppressive activity of MSR1⁺ TAMs is closely linked to their secretory profile. MSR1 enhances IL-6 secretion by activating the NF-κB signaling pathway, subsequently facilitating the recruitment of myeloid-derived suppressor cells (MDSCs). This cascade diminishes CD8⁺ T cell infiltration and effector function, promoting an immunosuppressive tumor microenvironment. In preclinical models, the simultaneous inhibition of MSR1 and PD-L1 markedly reduced tumor growth more effectively than either treatment alone. Our findings demonstrate that MSR1⁺ TAMs contribute to hepatocellular carcinogenesis through the NF-κB/IL-6 signaling axis by promoting MDSCs accumulation and impairing CD8⁺ T cell responses. Effectively targeting MSR1⁺ TAMs can overcome resistance to anti-PD-L1 therapy, offering a promising new immunotherapeutic approach for HCC.

Skin cancers, including melanoma, cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), present a fundamental paradox: high tumor immunogenicity coexists with profound immune evasion, driven by oncogenic signaling, an immunosuppressive microenvironment, metabolic dysregulation, and fibrotic stroma. Multifunctional nanoplatforms offer a systems-level strategy to overcome this multilayered resistance. They enable coordinated reprogramming of immune checkpoints and myeloid compartments, precise induction of immunogenic cell death through organelle-targeted stress or novel death pathways like cuproptosis, and synergistic use of photo-, ultrasound-, or magnetic-energy triggers. Concurrently, these platforms remodel the tumor microenvironment by scavenging immunosuppressive metabolites, exploiting lineage-specific metabolic vulnerabilities, and degrading fibrotic barriers to restore T-cell infiltration. The integration of computational intelligence-spanning AI-driven nanocarrier design, multi-omics-based patient stratification, and real-time biomarker monitoring-further empowers adaptive therapeutic strategies. By unifying biomimetic delivery, stimuli-responsive activation, and energy-coupled immunomodulation, advanced nanocarriers actively reconfigure tumor-immune crosstalk, demonstrating synergistic antitumor efficacy in preclinical models of melanoma, cSCC, and MCC. Successful clinical translation, however, requires addressing key challenges: scalable manufacturing of complex constructs, proactive management of cytokine-driven immunotoxicity, and robust biomarker-guided patient selection. The future of nano-immunotherapy lies in adaptive platforms that leverage liquid biopsy and computational modeling to dynamically counter the spatiotemporal evolution of resistance, offering a transformative paradigm for managing aggressive skin cancers.

Poor hematopoietic reconstitution (PHR), a serious complication after chemotherapy or radiotherapy in patients with hematological or solid malignancies, which lacks effective treatment options because its underlying pathogenesis remains unclear. Bone marrow macrophages (BM MΦs) are multifunctional, plastic cells essential in hematopoiesis though our previous study demonstrated distinct hematopoietic regulatory role between M1 and M2 subtypes. However, the specific phenotype of M2-MΦ and pathways involved in hematopoietic support remain unclear. Here, we identified a novel population of BM-MΦs, SELENOP⁺ MΦs, that exhibit an M2-biased phenotype with hematopoietic stem cell (HSC)-supporting ability. These cells were markedly impaired in patients with poor graft function (PGF) after allogeneic HSC transplantation, potentially because of defective autocrine GAS6-AXL (ligand-receptor) signaling. Both in vitro and BM MΦ-specific AXL knockdown mouse models confirmed that reduced AXL activity contributed to MΦ dysfunction and the downstream reduction in IGF1 secretion. Notably, treatment with GAS6 partially restored the HSC-supporting ability of impaired BM MΦ from PGF patients in vitro. Overall, our study identified an HSC-supportive SELENOP⁺ MΦ subset regulated by GAS6-AXL signaling, offering novel therapeutic insights for impaired hematopoiesis.

The hallmarks of cancer and enabling characteristics are widely regarded as the key features that best define malignant disease. In a process as intricate as the development of cancer, a simple definition or stepwise series of biological events does little to encapsulate the insurmountable complexity that is this disease. Indeed, over the course of the last 25 years alone, there have been four renditions of the "Hallmarks of Cancer", each attempting to encapsulate the mechanisms involved in the development of cancer by providing a list of strict criteria that must be met in order to define the disease. With each of these four sets of principles, modern research has caused the ensuing recapitulation to be revised, and without exception, to expand. In fact, what originally began as six hallmarks of cancer, has become a list of parameters that is fourteen strong, and which aim to summarize the functional capabilities that, when acquired by human cells, provides them with the ability to form a malignant, life-threatening tumour. While at present, these hallmark capabilities have largely been discussed in the context of all cancers, this review discusses each in the specific context of pancreatic cancer (PC). PC has the worst prognosis of all cancers globally, with late-stage diagnoses, aggressive tumour microenvironments, and limited treatment options contributing to the current 5-year survival rate of 13%. Here, we highlight PC-specific mechanisms underpinning each hallmark of cancer to provide a comprehensive review of the current state of knowledge around this complex disease, with the aim of aiding understanding and facilitating more meaningful research avenues.