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PubMed2025

A comprehensive reference catalog of human skin DNA virome reveals novel viral diversity and microenvironmental influences.

UNLABELLED: Human skin serves as a dynamic habitat for a diverse microbiome, including a complex array of viruses whose diversity and roles are not fully understood. A total of 2,760 skin metagenomes from 6 published skin studies were collected. A skin virome catalog was constructed using standard methods in the viromics field. Viral characteristics were identified through cross-cohort meta-analysis and used to characterize viral features across different skin environments. We identified 20,927 viral sequences, which clustered into 2,873 viral operational taxonomic units (vOTUs), uncovering a substantial breadth of viral diversity on human skin. The results also highlight significant differences in viral communities that are associated with varying skin microenvironments. The oily skin is enriched in Papillomaviridae, the dry skin area is enriched in Autographiviridae and Inoviridae, and the moist skin is enriched in Herelleviridae. We also investigated the relationship between bacteriophages and bacteria on the skin surface. We found that skin bacteria such as Pseudomonas, Klebsiella, and Staphylococcus are predicted to be infected by phages from the class Caudoviricetes. This comprehensive skin DNA viral catalog significantly advances our understanding of the virome's role within the skin ecosystem. IMPORTANCE: This study presents a comprehensive reference catalog of the human skin DNA virome, constructed from 2,760 metagenomic datasets collected globally. It identified 20,927 viral sequences, with 90.85% representing previously unknown viruses, greatly expanding our understanding of skin viral diversity. The findings reveal significant differences in viral communities between distinct skin microenvironments (oily, dry, and moist) and highlight close interactions between bacteriophages and their bacterial hosts, suggesting a potential role for the virome in maintaining microbial balance and skin health. This extensive skin viral catalog constitutes a crucial resource for future epidemiological and therapeutic research, potentially facilitating the development of novel phage therapies and diagnostic markers for skin disorders.

Humans↗

PubMed2026

Spatial biology reveals altered macrophage states in immunosuppressed non-melanoma skin cancer.

Immunosuppressed patients with non-melanoma skin cancer experience worse clinical outcomes, yet the tumor immune microenvironment associated with systemic immunosuppression remains incompletely defined. Using integrated single-cell, spatial transcriptomic, multiplex immunofluorescence, and spatial epigenomic profiling across immunocompetent and immunosuppressed tumors, we found that overall immune-cell composition was largely preserved despite differences in immune-cell distribution, spatial organization, and T cell clonality. Immunosuppressed tumors demonstrated reduced intratumoral macrophage densities, decreased T cell clonal diversity, altered antigen-presenting cell and T cell spatial interactions, and distinct fibroblast- and macrophage-associated spatial niches. Multi-cohort validation across complementary spatial and single-cell platforms identified consistent alterations in innate-adaptive immune organization in immunosuppressed tumors. Together, these findings define spatial and functional remodeling of the tumor immune microenvironment under systemic immunosuppression and provide a framework for future therapeutic investigation in high-risk patients.

Humans↗

PubMed2025

Intrinsic changes in cell differentiation and identity drive impaired wound healing in aged female murine skin.

Cellular and molecular mechanisms that drive a perturbed wound microenvironment and impaired healing in aged skin have not been fully delineated. To obtain a comprehensive understanding of cell-intrinsic changes acquired during ageing that impact early responses to injury, we performed single-cell RNA sequencing in young and aged intact female murine skin and wounds 3 days post-injury. We observed that substantial changes in the mean proportional distribution and transcriptomic state of skin resident subpopulations in aged, but not young, tissues accompany a global increase in basal inflammation. This is driven by an altered signalling environment leading to impaired keratinocyte differentiation, loss of fibroblast identity and defective macrophage function. Further, we show that ageing-induced changes in skin resident cells persist after injury, resulting in increased expression of senescence-related genes in wound fibroblasts and aberrant monocyte-to-macrophage transitioning coupled to an enhanced inflammatory signature and defective intercellular signalling in comparison to wounds in young mice. In summary, our data highlights a contribution of both cell-intrinsic changes and an altered tissue microenvironment to poor wound healing responses in aged mice.

Animals↗

PubMed2026

The mechanism of malignant progression in extramammary Paget's disease (EMPD): hallmarks of EMPD.

The pathogenesis of cancer is characterized by the acceleration of tumor growth, inhibition of tumor suppression, genetic and epigenetic alteration, lubricative transformation and tumor microenvironment. Extramammary Paget's disease (EMPD) is a rare skin cancer that originates from apocrine glands in genital and axillary area. Although the pathogenesis of EMPD is still poorly understood, increasing evidence reveals that the mechanism of EMPD progression is regulated by the acquired ability of EMPD cells and tumor microenvironment. HER2/PI3K/AKT signaling and hormone receptor pathways are activated. Whereas tumor mutation burden is low, numerous driver genes such as ERBB2 and PIK3CA are detected. Tumor evolution in EMPD is characterized by high genetic intratumor heterogeneity with shared background factors. Tumor microenvironment in EMPD promotes immune evasion through the reduction of reduced CD4 + and CD8 + T cells and the increase of Treg cells and CD163 + macrophages. Enhanced Warburg effect and S. aureus contribute to the suppression of antitumor immunity. This review focuses on the mechanism of malignant progression in EMPD (hallmarks of EMPD).

Genome mutation↗

PubMed2026

Proteomic and metabolomic profiling reveals dysregulation of immune states, mucin-type glycosylation and steroid metabolism in extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease is a rare cutaneous adenocarcinoma characterized by mucin-rich Paget cells and chronic inflammation, yet its molecular basis remains unclear. OBJECTIVE: To systematically characterize the proteomic and metabolomic landscape of EMPD, uncover immune heterogeneity, and identify molecular pathways underlying tumor progression and microenvironment remodeling. METHODS: We performed integrated proteomic and metabolomic analyses on 92 male tumor patients and 30 healthy controls, identifying 10,217 proteins and 1466 metabolites. RESULTS: Extramammary Paget's disease lesions exhibited broad activation of inflammatory pathways. Immune profiling further uncovered substantial inflammatory heterogeneity, delineating immune-cold and immune-hot subtypes, with the latter associated with stronger invasive potential. Aberrant mucin-type glycosylation was also prominent, featuring Tn-modified MUC1 and MUC5AC accompanied by elevated GALNT7, GALNT6, GALNT4, and ST6GAL1, which correlated with inflammatory intensity. Metabolomic data demonstrated elevated levels of testosterone, dehydroepiandrosterone, and related intermediates in tumor tissues, indicating an androgen-enriched metabolic profile in extramammary Paget's disease. CONCLUSION: These findings reveal immune, glycoproteomic, and metabolomic pathways in extramammary Paget's disease pathogenesis and provide novel insights for molecular classification and therapeutic targeting.

Humans↗

PubMed2026

Dual-Reporter Gene-Based Multimodal Imaging for Tracking Mesenchymal Stem Cells in Diabetic Skin Wound Repair.

BACKGROUND: Diabetic foot ulcer (DFU) is a clinically challenging complication characterized by poor healing outcomes, and conventional therapies provide limited benefit. Mesenchymal stem cell (MSC) transplantation offers a promising strategy for DFU repair. However, the low survival of transplanted MSCs in the hostile wound microenvironment, coupled with the lack of real-time, non-invasive methods to track these cells in vivo, severely hampers their therapeutic efficacy and clinical translation. METHODS: We engineered MSCs to co-express a dual reporter system comprising near-infrared fluorescent protein (iRFP) and ferritin heavy chain (FTH1). These modified cells were then integrated with a fibrin glue (FG) scaffold to create a unified platform that supports both multimodal imaging and therapeutic function within skin wounds. First, FTH1 overexpression enhances the antioxidant capacity of MSCs, while the FG scaffold provides structural support; this combination enhances cell survival and retention. Second, the iRFP/FTH1 dual reporter enables near-infrared fluorescence imaging and MRI-based localization, establishing a multimodal platform for real-time cell tracking. RESULTS: In a full-thickness skin defect model in diabetic mice, multimodal imaging revealed that transplanted cells persisted in the wound area for approximately seven days. Treatment with iRFP/FTH1-MSCs/FG significantly accelerated wound closure and promoted hair follicle regeneration and angiogenesis. Additionally, local iron deposition resulting from FTH1 expression enhanced fibroblast migration and collagen synthesis, further facilitating extracellular matrix remodeling. Mechanistic studies demonstrated that this therapy drives macrophage polarization toward the anti-inflammatory M2 phenotype and activates the PI3K-AKT-VEGF signaling pathway. These complementary effects synergistically enhance tissue regeneration and systematically improve diabetic wound healing. CONCLUSIONS: Collectively, this multimodal stem cell-scaffold system effectively integrates dynamic cell tracking with stem cell therapy during skin wound repair. It addresses a critical technical gap in visualizing stem cells within the wound microenvironment and provides valuable methodological and theoretical foundations for optimizing regenerative strategies for diabetic skin wounds.

Animals↗

PubMed2026

IL1RAP Is Associated With an Inflammation-Immunity-Related State in Skin Cutaneous Melanoma: Integrative Evidence From Pan-Cancer Data and Melanoma Immunotherapy Cohorts.

BACKGROUND: The crosstalk between inflammation and immunity plays a central role in tumor progression, immune evasion, and therapeutic response. Interleukin-1 receptor accessory protein (IL1RAP) is a key adaptor in inflammatory signaling, yet its immunological relevance and clinical implications in skin cutaneous melanoma (SKCM) remain largely unexplored. METHODS: We performed an integrative analysis combining pan-cancer and melanoma-focused datasets. Bulk transcriptomic, single-cell, spatial transcriptomic, genomic alteration, pharmacogenomic, and clinical survival data were obtained from TCGA, GTEx, GEO, ENA, and other public resources. IL1RAP expression was evaluated across cancer types in relation to diagnostic performance, immune subtypes, survival outcomes, functional pathway activity, immune-genomic states, somatic alterations, and drug-response metrics. Melanoma-focused analyses examined immune infiltration, methylation-derived tumor-infiltrating lymphocyte (MeTIL) scores, and exploratory survival associations in five treatment cohorts; the survival groups were defined using cohort-specific optimal cutoffs rather than median splits. RESULTS: IL1RAP expression differed between tumor and normal tissues in multiple cancers, although the direction and magnitude varied by cancer type. Pan-cancer survival associations were likewise context dependent. Single-cell and spatial transcriptomic resources indicated cell-type and spatial heterogeneity of IL1RAP expression within tumor microenvironments. Pathway, immune-genomic, and pharmacogenomic analyses identified exploratory associations with functional states, genomic features, and drug-response metrics. In SKCM, IL1RAP expression was associated with several immune-infiltration estimates and higher MeTIL scores. Across five melanoma immunotherapy cohorts, the direction and magnitude of the overall survival associations varied substantially. CONCLUSIONS: This retrospective integrative analysis suggests that IL1RAP may mark an inflammation-immunity-related state in SKCM. The heterogeneous associations across cancers and melanoma treatment cohorts support further validation but do not establish IL1RAP as a causal regulator, a treatment-response predictor, or a therapeutic target.

IL1RAP↗

PubMed1977

Fever and behavioural temperature regulation in the frog Rana esculenta.

The skin and colonic temperatures were recorded in frogs (Rana esculenta) which had selected a suitable microenvironment in a box filled with 2-3 cm water. The water temperatures ranged from 0 degrees C to + 40 degrees C. Such measurements were performed before and after intraperitoneal injections of killed pathogenic bacteria (M. xenopi and M. range), killed non-pathogenic bacteria (M. aquae II) and 0.9% sterile saline, intraperitoneal injections of blood plasma from frogs pre-injected with killed M. ranae, injections of PGE1 into the brain. The injections of pathogenic bacterial endotoxin caused, after latencies of 5-120 min, higher preferred water temperatures, which produced an average maximum colonic temperature increase of 6.5 degrees C +/- 1.0 degrees C (S.E.) (p less than 0.001). The non-pathogenic bacteria and sterile saline caused no temperature change. Monophasic hyperthermia of shorter latency was caused by injections of blood plasma from frog preinjected with M. ranae. Monophasic hyperthermia of the shortest latency was observed after diencephalic injections of PGE1. Based on their similarity we suggest that ectothermic and endothermic fever have a common phylogenetic origin.

Animals↗

PubMed2025

Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

Animals↗

PubMed2026

A machine learning-derived intratumoral heterogeneity-related signature predicts the prognosis for and therapeutic response in patients with skin cutaneous melanoma.

BACKGROUND: Reliable biomarkers for predicting prognosis and therapeutic response in skin cutaneous melanoma (SKCM) remain limited. This study aimed to develop an intratumoral heterogeneity (ITH)-related prognostic signature for SKCM using integrative machine learning. METHODS: RNA sequencing (RNA-seq) data from 472 SKCM patients in The Cancer Genome Atlas (TCGA) and 214 patients in the GSE65904 cohort were analyzed. ITH scores were calculated using the DEPTH2 algorithm. Differentially expressed genes (DEGs) were identified between high- and low-ITH groups [|log2fold change (FC)| ≥1, false discovery rate (FDR) <0.05]. Based on 38 prognostic DEGs identified by univariate Cox regression, we employed an integrative framework of 101 machine learning algorithm combinations to construct prognostic models in the TCGA training cohort. The model with the highest average concordance index (C-index) was validated in the GSE65904 cohort and selected as the prognostic ITH-related signature (PIRS). Associations of the PIRS risk score with tumor mutational burden (TMB), immune cell infiltration, immune checkpoint gene expression, and drug sensitivity were systematically evaluated. Model performance was assessed using receiver operating characteristic (ROC) curves and Cox regression analyses. RESULTS: A 38-gene PIRS was constructed using the plsRcox algorithm. Patients with high PIRS risk scores exhibited significantly poorer overall survival (OS) in both the TCGA and Gene Expression Omnibus (GEO) cohorts. The PIRS was identified as an independent prognostic factor, with area under the curve (AUC) values of 0.779, 0.734, and 0.756 for 1-, 3-, and 5-year survival, respectively. High-risk samples displayed significantly lower TMB (P<0.05), reduced immune and stromal cell infiltration (P<0.001), downregulated immune function, and decreased expression of immune checkpoint genes. Additionally, high- and low-PIRS risk score groups exhibited distinct sensitivity patterns to different classes of targeted agents. CONCLUSIONS: The machine learning-derived PIRS robustly predicts prognosis in SKCM patients. Its clinical application is promising for optimizing patient risk stratification and treatment decisions, though further prospective validation is warranted.

Skin cutaneous melanoma (SKCM)↗

PubMed2026

Topical Donepezil for Cholinergic Modulation in Chronic Wound Repair.

Chronic wounds result from combined defects in vascular perfusion, inflammatory resolution, and epithelial repair. The skin's non-neuronal cholinergic system (NNCS), formed by keratinocytes, endothelial cells, fibroblasts, and immune cells that synthesise and respond to acetylcholine (ACh), helps coordinate these processes through muscarinic and nicotinic receptors. Inhibition of acetylcholinesterase (AChE) increases local ACh concentrations and may engage two key pathways supported by preclinical data: M3 muscarinic receptor (M3 mAChR)-endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-mediated vasodilation, and α7 nicotinic acetylcholine receptor (α7-nAChR)-mediated suppression of pro-inflammatory cytokines. Donepezil is a reversible, selective AChE inhibitor with physicochemical properties compatible with dermal administration. Low-dose or microneedle dermal delivery has produced dermal exposure with limited systemic uptake in animal and ex vivo skin studies. In preclinical diabetic wound models, nicotinic receptor activation accelerated healing, reduced inflammatory signalling, and improved control of bacterial burden. We hypothesise that topical donepezil formulated for localised dermal delivery could restore cholinergic signalling within the wound microenvironment by increasing local ACh concentrations. This approach may complement metabolic therapies that support arginine-NO coupling and redox balance. Controlled pilot studies should assess local cutaneous pharmacodynamics, perfusion responses, and wound-closure outcomes.

Donepezil↗

PubMed2026

Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.

Cancer arises from genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To chart cancer-intrinsic regulatory programs, we build a pan-cancer single-cell atlas of 60 cancer cell lines spanning 16 tissue origins and 20 cancer types, comprising 240,957 snRNA-seq and 223,347 snATAC-seq profiles. Integrative analyses reveal cell-state heterogeneity, core gene-regulatory networks, and a conserved EMT axis transcending tissue of origin; copy-number analysis identifies transcription factor amplification and hyperactivation as drivers of state reprogramming. Comparing cutaneous melanoma with acral melanoma, a rare subtype underrepresented in previous studies, uncovers a universal inflammation-suppressive program in acral and an inflamed landscape in cutaneous melanoma, with JAK-STAT activity as the central discriminator. Integrating data across models and patient cohorts links tumor-intrinsic regulation to microenvironmental composition and therapeutic response. By profiling rare alongside common subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific regulatory programs shaping cell-state plasticity.

Humans↗

PubMed1979

Effects of hormonal therapy on the microbiology of seborrheic dogs.

Quantitative and qualitative bacterial assays were performed on the skin of three dogs with endocrine-related primary metabolic seborrhea. After the dogs were treated (thyroid supplementation or castration, bacterial analyses were again performed on the same sites. Before therapy, the dogs had a cutaneous flora composed mainly of Staphylococcus aureus coagulase-positive organisms. After therapy, there was a significantly lower bacterial count, and two of the dogs had floras consisting mainly of coagulase-negative cocci. During the study, the two dogs that reverted bacteriologically to a normal cutaneous microenvironment became normal dermatologically. The third dog improved, but continued to have minor signs of seborrhea.

Animals↗

PubMed1977

The ultrastructure of mycosis fungoides, of Sezary's syndrome, and of Woringer-Kolopp's disease (pagetoid reticulosis).

Skin lesions of 13 cases of mycosis fungoides, 2 cases of Sézary's syndrome and one case of Woringer-Kolopp's disease were studied. In mycosis fungoides two main cell types were observed: small atypical lymphoid cells, and large atypical lymphoid cells. The small atypical lymphoid cells were characterized by dense nuclei with varying degrees of nuclear lobulation. Normal-appearing lymphocytes and typical mycosis cells were in this cell group. The large atypical lymphoid cells were characterized by large nuclei with little lobulation and by less chromatin condensation, as well as by a more abundant cytoplasm. Their identification is discussed and indications of their possibly being neoplastic or proliferating lymphoblasts are given. In Sézary's syndrome Sézary cells with more lobulated nuclei than in mycosis cells and lymphoblast-like cells as in mycosis fungoides could be found. In Woringer-Kolopp's disease cells similar to Sézary cells aggregated mainly in the epidermis. No interdigitating reticulum cells and no other morphological signs of a specific lymphocyte microenvironment were found in any of the cases.

Dermatitis, Exfoliative↗

PubMed2026

Impact of NR4A3 on wound healing in chronic venous ulcers and its association with the PI3K/Akt signaling pathway.

BACKGROUND: To investigate the role of NR4A3 in chronic venous ulcer (VU) wound healing and to explore its potential regulatory mechanism involving the PI3K/Akt pathway. METHODS: Differential expression and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the GSE174661 dataset. DEGs were filtered by |log2FC| > 1 and adjusted P < 0.05, with KEGG significance set at P < 0.05. NR4A3 was identified as the core gene. NR4A3 knockdown and overexpression were established in HaCaT cells to evaluate proliferation, migration, and inflammatory cytokines. TNF-α was used to mimic the inflammatory microenvironment. Western blotting assessed phosphorylation of GSK3β, mTOR, PI3K, and Akt. PI3K/Akt agonist 740Y-P and inhibitor LY294002 were used in rescue experiments. RESULTS: Bioinformatic analysis revealed that NR4A3 expression was markedly downregulated in chronic venous ulcer (VU) tissues relative to normal skin and ordinary acute wound tissues. Differentially expressed genes were significantly enriched in the PI3K/Akt signaling pathway. TNF-α stimulation significantly upregulated NR4A3 expression and increased phosphorylation of GSK3β and mTOR in HaCaT cells. In cultured HaCaT keratinocytes, NR4A3 knockdown suppressed cell proliferation and invasion, enhanced cell migration, and elevated the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8, CXCL5), accompanied by reduced phosphorylation of PI3K and Akt. Conversely, NR4A3 overexpression promoted cell proliferation and invasion, restrained migration, and dampened inflammatory responses, while increasing PI3K/Akt phosphorylation. Treatment with the PI3K/Akt agonist 740Y-P partially rescued the impaired proliferation, aberrant migration, and excessive inflammation caused by NR4A3 silencing, whereas PI3K/Akt inhibitor LY294002 aggravated pathway suppression. These findings suggest that NR4A3-associated changes in keratinocyte functions and inflammatory reactions are functionally linked to PI3K/Akt pathway activity, and inflammatory stimulation activates GSK3β/mTOR signaling accompanied by compensatory NR4A3 upregulation. CONCLUSION: These findings suggest that NR4A3 is associated with keratinocyte behavior and inflammatory responses via the PI3K/Akt pathway, potentially affecting chronic VU progression and healing. Reduced NR4A3 may impair wound repair through inflammation and abnormal cell migration, while TNF-α induces compensatory NR4A3 elevation.

NR4A3↗

PubMed1979

Microenvironmental influences on the in vivo behavior of neoplastic lymphocytes.

A transplantable hamster lymphocytic neoplasma of probable monoclonal derivation, induced by the oncogenic DNA simian virus 40, has been adapted to grow in the allogeneic host either as leukemia (characterized by dissemination and poor prognosis) or as lymphoma (characterized by localization and favorable prognosis) [Diamandopoulos, G. Th. (1978) Proc. Natl. Acad. Sci. USA 75, 2011-2015]. In the present experiments the circumstances under which neoplastic lymphocytes that are transplanted in allogeneic animals retain, lose, or regain the capacity for dissemination or localization are assessed. Results indicate that the in vivo behavior of neoplastic lymphocytes is not a stable, irreversible characteristic that is transmitted to the cell progeny. On the contrary, it can be altered by the origin/tissue microenvironment in which the cells proliferate. It is suggested that, whereas neoplastic cell mutation followed by host selection could be responsible for changes in cell behavior, a more likely explanation is that the proliferating neoplastic lymphocytes acquire reversible nonmutational phenotypic characteristics during their interaction with the host microenvironment, which modify their behavior and, as a result, the prognosis of the neoplastic process.

Animals↗

PubMed2026

Myeloid-Mediated Immunoregulation and Resistance to Immune Checkpoint Inhibitor Therapy Across Squamous Cell Carcinomas: Mechanisms and Reprogramming Strategies.

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically "cold" tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3Kγ, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites.

dendritic cells↗

PubMed1975

Effect of antithymocyte globulin pretreatment on immunological reconstitution of lethally irradiated animals.

Clinical and experimental studies have shown that antithymocyte globulin pretreatment will reduce the severity of the graft-versus-host reaction after allogeneic bone marrow transplantation. To determine whether this was attributable to a persisting cytotoxic factor in the recipients' sera or a result of the "masking" of foreign antigens by the antihymocyte globulin, an experimental schema utilizing a syngeneic transfer of immunocompetent cells was devised. Lethally irradiated mice that had been pretreated with rabbit antimouse thymocyte globulin (RAMTG) were injected with syngeneic spleen or bone marrow cells and their immunological competence was measured by the response to a test antigen, sheep red blood cells. It was found that such pretreatment had an adverse effect on the immunological potential of the infused cells. Thus, the plaque-forming cell response to sheep red blood cell antigen in RAMTG-pretreated recipients injected with spleen cells was reduced when compared to the saline or normal rabbit globulin-treated controls. The immunological recovery of lethally irradiated animals protected with syngeneic bone marrow was also delayed, but not permanently impaired, when the recipients had been pretreated with RAMTG. These effects were evident although the spleen or bone marrow cells had been injected into the RAMTG-pretreated recipients at a time when their sera were devoid of any cytotoxic antibodies. It is speculated that two mechanisms may contribute to this alteration in immune function of the infused cells: (1) that RAMTG exists in the serum in amounts sufficient to attach to receptor sites on lymphocytes or their precursors but insufficient to kill the cells, interfering with the antigen recognition mechanism or migration and homing patterns, or (2) that the RAMTG treatment creates a temporary defect in the microenvironment of the spleen and other hemopoietic tissues, thereby affecting the transplantation and proliferation kinetics of the infused cells.

Animals↗