Search Results (7,957)

Radiation-induced morphea (RIM) is a rare, immune-mediated late complication of breast radiotherapy that may clinically mimic radiation fibrosis, malignancy, or other inflammatory dermatoses. Diagnosis is particularly challenging in patients with pre-existing cutaneous T-cell lymphoma (CTCL), in whom new post-radiation skin lesions may raise concern for lymphoma involvement or progression. To the best of our knowledge, based on a non-systematic search of the available literature, this is the first reported case of radiation-induced morphea occurring in a patient with pre-existing mycosis fungoides (MF). A 55-year-old woman with a history of MF and right breast invasive lobular carcinoma underwent bilateral mastectomy followed by adjuvant chest wall radiotherapy. Approximately 6.5 years later, she developed a progressive erythematous, indurated plaque within the irradiated field. Given her history of MF, cutaneous lymphoma involvement and radiation-associated sarcoma were important diagnostic considerations. Punch biopsy demonstrated dermal collagen homogenization with a mixed inflammatory infiltrate, while immunohistochemistry showed preserved pan-T-cell antigen expression without an aberrant phenotype, supporting RIM rather than lymphoma. The patient was treated with topical corticosteroids followed by methotrexate, with mild-to-moderate improvement in erythema without complete resolution; subsequent reconstructive revision was followed by further improvement in erythema, breast softness, and cosmesis. This case highlights the diagnostic overlap between RIM and CTCL and underscores the importance of prompt biopsy and careful clinicopathological correlation in evaluating persistent or atypical post-radiation skin changes. Full article

Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is characterized by type 2 inflammation, including M2 macrophage infiltration. Baicalein is a flavonoid with anti-inflammatory properties. This study aimed to investigate the therapeutic effect of baicalein in a papain-induced eosinophilic rhinosinusitis model and to determine whether it acts through arachidonate 15-lipoxygenase (ALOX15)-dependent M2 macrophage function. Clinical nasal samples from controls, non-eosinophilic CRSwNP (neCRSwNP), and eCRSwNP were analyzed for ALOX15 expression and localization. THP-1 cells were differentiated and polarized toward M2 macrophages, and the effects of baicalein on ALOX15 expression, lipid peroxidation, cytokine secretion, and transcriptomic profile were examined. The ALOX15 inhibitor PD146176 was used for target validation. A murine eosinophilic rhinosinusitis model was established by intranasal papain instillation, followed by baicalein treatment. Mucosal inflammation, IgE levels, proteoglycan 2 (PRG2)/ALOX15 expression, and immune cell infiltration were evaluated. ALOX15 was upregulated in eCRSwNP tissues and localized to CD68⁺CD206⁺ M2 macrophages. In vitro, M2 polarization increased ALOX15 expression and lipid peroxidation. Baicalein suppressed ALOX15 expression, lipid peroxidation, and the secretion of CCL22, CCL2, CXCL12, FGF-2, and IL-15. PD146176 produced similar effects, and baicalein showed no additional effect after ALOX15 blockade. RNA sequencing revealed transcriptional remodeling in M2 macrophages after baicalein treatment. In vivo, papain increased ethmoid sinus mucosal thickening, serum IgE, PRG2/ALOX15 positive cells, and infiltration of CD45⁺ immune cells, CD170⁺ eosinophils, F4/80⁺ macrophages, and B220⁺ B cells. Baicalein significantly alleviated all these pathological changes. In conclusion, baicalein attenuates papain-induced eCRSwNP-like inflammation by inhibiting lipid peroxidation and ALOX15-associated M2 macrophage secretory function. The ALOX15/M2 macrophage axis may represent a potential therapeutic target for eCRSwNP. Full article

Background/Objectives: The development of multifunctional biomaterials for bone regeneration remains a key challenge in additive manufacturing. Although polylactic acid (PLA) is widely used in fused deposition modeling (FDM), its limited bioactivity and lack of intrinsic antibacterial functionality restrict its application in implantable constructs. This study aimed to develop a PLA-based composite filament combining ion-mediated bioactive potential and local antibacterial functionality using a Quality by Design (QbD) approach. Methods: PLA-based composite filaments incorporating a mollusk shell-derived biogenic calcium-containing filler (20 wt.%) and gentamicin (5 wt.%) were fabricated by solvent-free melt extrusion. A QbD framework was applied to define the Quality Target Product Profile (QTPP), identify critical quality attributes (CQAs), and assess critical material attributes (CMAs) and critical process parameters (CPPs). The material was characterized by SEM–EDS combined with ImageJ-based quantitative image analysis, TGA/DSC, mechanical testing, ICP-AES analysis of aqueous extracts, agar diffusion antibacterial assays, FDM printability assessment, and in vivo biocompatibility testing in a rat subcutaneous implantation model. Results: The developed PLA–Gen–MS material was obtained as a continuous filament with a diameter of 1.75 ± 0.05 mm and was successfully used for FDM printing of model scaffold structures. SEM–EDS confirmed matrix continuity and distribution of the calcium-containing mineral phase. ICP-AES revealed a calcium-dominant multicomponent ion release profile, with Ca as the predominant element and measurable levels of Sr, Mg, P, Mn, and Fe. TGA/DSC confirmed thermal compatibility of the components under melt-processing conditions. PLA–Gen–MS demonstrated antibacterial activity against all tested strains, with inhibition zones of approximately 20–21 mm. In vivo, the material showed a favorable preliminary tissue response compared with TiLOOP^®, including faster reduction of inflammatory infiltration and absence of foreign body giant cells by day 14. Conclusions: The QbD-guided strategy enabled the development of a multifunctional PLA-based filament integrating melt processability, structural integrity, ion-mediated bioactive potential, antibacterial functionality, printability, and favorable preliminary biocompatibility. PLA–Gen–MS can be considered a promising platform for further development of personalized bioactive and antibacterial scaffold constructs for bone regeneration. Full article

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality owing to late diagnosis, aggressive tumor biology, and limited clinically useful early diagnostic and prognostic biomarkers. This study provides an exploratory evaluation of the expression profile, survival associations, co-expressed genes, functional association networks, and regulatory relationships of MEAK7 (KIAA1609/TLDC1) in pancreatic cancer using multi-platform bioinformatic approaches. We conducted a comprehensive multi-platform bioinformatic analysis using multiple publicly available datasets and platforms, including TCGA/GTEx, GEO, GEPIA3, HPA, CPTAC/UALCAN, TNMplot, Kaplan–Meier Plotter, DoSurvive, TIMER 3.0, STRING, TargetScan, miRDB, ENCORI and lncRNADisease. Gene expression patterns, survival associations, immune cell infiltration and regulatory non-coding RNA networks were systematically investigated. A STRING-derived protein functional association network was evaluated. MEAK7 expression patterns were additionally assessed in external GEO datasets, including GSE62165, GSE71729, and GSE183795. In summary, MEAK7 expression was elevated in pancreatic cancer compared with normal pancreatic tissues, was detectably expressed across multiple pancreatic cancer cell lines, and was increased in patient-derived PDAC samples. ROC analysis showed that MEAK7 expression discriminated PDAC tumor tissues from adjacent non-tumor pancreatic tissues, with an AUC of 0.795 (95% CI: 0.719–0.871) indicating exploratory transcriptomic discrimination rather than clinical diagnostic performance. Exploratory survival analyses showed that elevated MEAK7 expression was associated with unfavorable overall survival and disease-free outcomes, while multivariable Cox analyses showed that this association persisted after adjustment for the covariates available within the analyzed dataset. GEO-based analyses supported increased MEAK7 expression in early-stage pancreatic cancer samples, although metastatic expression patterns varied across datasets. Correlation and interaction analyses revealed positive associations between MEAK7 and PDAC-related genes, including CTTN, CDCP1, SMARCA4, SFN, and PALB2, as well as high-confidence STRING functional associations with V-ATPase components and RNASEK. Furthermore, MEAK7 was positively correlated with lncRNA UCA1 and negatively correlated with miR-582-5p. Collectively, these findings identify reproducible expression and survival-associated patterns involving MEAK7 across the analyzed datasets and provide a hypothesis-generating framework for further investigation of its potential biological role in PDAC. Experimental studies and prospectively characterized patient cohorts are required before any clinical, prognostic, diagnostic, or therapeutic implications can be established. Full article

This review summarises current evidence on renal cell carcinoma (RCC) with sarcomatoid dedifferentiation (sRCC), with an emphasis on diagnosis, prognostic stratification, and treatment. Sarcomatoid dedifferentiation is characterised by high-grade spindle cell morphology, occurs in 2–26% of all RCC patients, predominantly in the clear cell subtype (~70%), and is WHO/ISUP grade 4 regardless of extent of involvement. Thus, sRCC represents a pathological transformation rather than a distinct entity. Diagnosis requires biopsy or nephrectomy; immunohistochemical (IHC) retention of PAX8, cytokeratins, and vimentin alongside loss of subtype-specific markers distinguishes sRCC from primary renal sarcoma. On CT, sRCC typically presents as a large, heterogeneous mass with extensive necrosis; 18F-FDG PET/CT carries independent prognostic value, though no feature is pathognomonic. Sarcomatoid features are approximately five times more prevalent in patients with metastatic vs. localised disease (~20 vs. ~4%), and their identification should prompt risk stratification. Median overall survival (OS) in metastatic sRCC is 5.9–13.3 months, though recent data suggest improvement with novel therapies. Sarcomatoid dedifferentiation is characterised by enrichment of alterations in TP53, BAP1, CDKN2A/B, and NF2 on a background of founder RCC mutations, generating an immune-inflamed tumour microenvironment with elevated CD8+ T cell infiltration and PD-L1 expression that may underpin the heightened sensitivity of sRCC to immune checkpoint inhibitors (ICI). Surgery remains the cornerstone in localised disease, although recurrence rates approach 80% within two years. Adjuvant pembrolizumab significantly improved disease-free survival in high-risk localised RCC with sarcomatoid features (KEYNOTE-564; NCT03142334). In the metastatic setting, nivolumab plus ipilimumab and pembrolizumab plus axitinib are preferred first-line regimens. Full article

Aortopathies in autoimmune rheumatic diseases (ARD) include a spectrum of aortic pathologies—including aortitis, aneurysms, dissections, and insufficiency—primarily caused by systemic inflammation. This comprehensive review investigates the clinical manifestations, pathophysiology, diagnostic modalities, and management strategies across various rheumatic diseases associated with aortopathies such as large vessel vasculitis (e.g., Takayasu arteritis, giant cell arteritis), connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis) and less common conditions (e.g., relapsing polychondritis, Cogan’s syndrome, Behçet’s disease, IgG4-related disease). Disease-specific pathophysiologic mechanisms of aortic wall inflammation and remodeling, including granulomatous and lymphoplasmacytic patterns and mixed inflammatory infiltrates, are described. Diagnostic imaging modalities—such as CTA, MRI, and PET/CT—are evaluated for their roles in detecting active inflammation, assessing structural complications, and guiding clinical decision-making. Histopathological findings provide insight into disease-specific vascular changes. Management strategies focus on the use of glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and biologics, including IL-6 and TNF-α inhibitors, with an emphasis on patient-centered approaches, multidisciplinary care, and timely surgical intervention for complications. Evidence gaps include optimal screening intervals and the role of novel biomarkers in risk stratification and in monitoring disease progression, highlighting the need for early recognition, frequent monitoring, and aggressive management of aortic involvement in rheumatic diseases to prevent life-threatening complications. Full article

Background: The immune landscape in head and neck squamous cell carcinoma (HNSCC) has been widely investigated. However, the crucial role played by the lymph node microenvironment in metastatic and non-metastatic HNSCC remains unknown. This systematic review aims to discuss the immunological crosstalk between the tumor and the nodal microenvironment and to describe the distribution of immune cells in metastatic and non-metastatic lymph nodes. Methods: A systematic review was conducted according to the PRISMA guidelines. PubMed, Scopus, and the Cochrane Library were searched for studies published between 1990 and 2025, with the final search performed in December 2025. Prospective and retrospective studies evaluating immune cell infiltration in metastatic and non-metastatic cervical lymph nodes were included, whereas studies focusing exclusively on non-cellular biomarkers and non-English publications were excluded. The risk of bias was assessed using the Newcastle–Ottawa Scale. The results were synthesized narratively, and no meta-analysis was performed. Results: The screening process identified 608 articles, of which 27 met our predefined inclusion criteria. These studies focused on macrophages, dendritic cells, neutrophils, natural killer cells, T helper cells, cytotoxic T cells, regulatory T cells, B cells, total lymphocytes, and surface markers. This systematic review provides a well-structured analysis of current knowledge on the impact of the innate and adaptive immune systems on the response against cancer cells and the recruitment of immune cells in lymph nodes. The most significant findings highlight the crucial role of antigen presentation in the antitumor response, particularly through the recruitment and activation of dendritic cells and subcapsular sinus macrophages in tumor-draining lymph nodes. It also presents in a fairly comprehensible manner that the density of mature dendritic cells, cytotoxic T cells, and B cells is higher in non-metastatic lymph nodes. Discussion: The lymph node microenvironment is highly enriched with immune cell infiltration, and their distribution between metastatic and non-metastatic lymph nodes can contribute to a better understanding of the underlying pathological processes. Particular attention should be given to the innate immune system cells and their implication in antigen presentation. Our findings suggest that identifying immunological profiles of lymph nodes may provide a rationale for treatment de-escalation protocols and raise the question of lymph node preservation in antitumor immune responses. However, the heterogeneity and bias assessment of the included studies warrant a cautious interpretation of these findings. Another important limitation is the limited number of studies comparing the immune microenvironment of primary tumors and lymph nodes. Full article

Urban particulate matter (UPM) is a major environmental pollutant known to induce systemic inflammation. While its respiratory toxicity is well-documented, the potential vulnerability of the female reproductive system to inhaled UPM remains a critical concern. In this study, we evaluated female reproductive outcomes in a murine model following repeated short-term intratracheal instillation of UPM (40–200 mg/kg) for a month. Our results demonstrate that while UPM exposure induced robust, dose-dependent pulmonary inflammation, characterized by immune cell infiltration (CD45+, F4/80+, and Ly6G+) and upregulation of pro-inflammatory (Il-6, Il-1β, and Tnfα) and fibrotic (Col1a1 and Tgfβ1) markers, no apparent adverse effects were observed in the reproductive endpoints examined. No significant alterations were observed in maternal pregnancy outcomes, including oocyte recovery rates, fertilization competence, gestation duration, litter size, and postnatal development of pups. Furthermore, the mRNA expression of inflammatory markers in the ovaries and uteri was not detectable. Direct in vitro exposure of two-cell embryos to UPM did not interfere with preimplantation embryo development. Although benzanthracene slightly reduced the blastocyst formation rate, UPM and polycyclic aromatic hydrocarbons, major toxic components of UPM, did not severely compromise preimplantation embryo development in vitro. In conclusion, these findings suggest that marked UPM-induced pulmonary inflammation is not accompanied by substantial alterations in the female reproductive outcomes examined under short-term exposure conditions. Full article

Tumor-infiltrating lymphocyte (TIL) therapy is the first adoptive cellular therapy approved to treat solid tumors and has demonstrated durable responses in advanced melanoma. However, its clinical implementation is limited by the need for tumor harvesting, manufacturing delays, and lymphodepleting conditioning. These logistic challenges are also opportunities for physicians and scientists to consider combining TIL therapy with radiation therapy (RT), a modality with well-established roles in cancer care. RT exerts both immunostimulatory and immunosuppressive effects, influencing antigen presentation and T-cell trafficking while also contributing to lymphocyte depletion in a dose- and context-dependent manner. These properties provide a strong biologic rationale for integration with TIL therapy but also introduce important uncertainties. Preclinical studies suggest RT can enhance TIL expansion and function, while early clinical experience supports the feasibility of RT delivery before and after TIL therapy in selected scenarios. However, prospective clinical data remain limited, and key questions regarding optimal timing, dose, and target selection are unresolved. In this review, we propose a workflow-based framework for combining RT with TIL therapy across pre-harvest, bridging, peri-infusion, and post-infusion settings. RT is a promising partner to TIL therapy, but prospective studies will ultimately be needed to define how best to integrate RT in order to translate biologic synergy into consistent clinical benefit. Full article

Familial hypercholesterolemia (FH) has been associated with an increased risk of major depressive disorder (MDD), but their shared molecular signatures remain unclear. This study aimed to identify candidate genes associated with FH-MDD co-occurrence through integrative transcriptomic analysis, machine learning, summary-data-based Mendelian randomization (SMR), and clinical validation. Transcriptomic datasets from the Gene Expression Omnibus were analyzed, including GSE6054 and GSE13985 for FH and GSE98793 for MDD. Differential expression analysis and weighted gene co-expression network analysis were used to identify shared candidate genes. Candidate biomarkers were screened using least absolute shrinkage and selection operator regression and Random Forest algorithms, followed by the construction of an exploratory nomogram. SMR analysis was performed to assess genetically supported associations between candidate-gene expression and MDD risk. Selected genes were validated by PBMC RT-qPCR in an independent four-group clinical cohort comprising healthy controls and participants with FH, MDD, or co-occurring FH and MDD. Flow cytometry was subsequently used to characterize the peripheral CD4+ T-cell profile. A total of 54 shared candidate genes were identified. CD4, MRPS21, and CRTC2 were selected by machine learning and incorporated into the nomogram, which showed good discrimination in the training set and moderate performance in external validation. Immune infiltration and enrichment analyses highlighted monocyte alterations, reduced T-cell-related signals, and enrichment of T-cell receptor and TNF-mediated pathways. SMR analysis indicated that genetically predicted higher CD4 expression was inversely associated with MDD risk, whereas RT-qPCR showed higher CD4 expression in patients with FH-MDD. Flow-cytometric analysis showed that FH-MDD participants had a higher circulating CD3+CD4+ T-cell proportion, an increased effector-memory CD4+ T-cell proportion, and a higher proportion of HLA-DR+ CD4+ T cells than participants in the comparison groups. These findings suggest that CD4 may represent a promising immune-related candidate signature associated with the co-occurrence of FH and MDD, warranting further functional validation. Full article

Background/Objectives: Chimeric antigen receptor (CAR)-T cell therapy has achieved substantial clinical success in haematological malignancies but has shown limited efficacy against solid tumours. Key barriers include inadequate tumour trafficking, immunosuppressive tumour microenvironments, poor selectivity and heterogeneity of antigen expression, and challenges related to safety and manufacturing. Biomaterial-based technologies have emerged as a potential strategy to address many of these limitations. This review aims to critically evaluate biomaterial approaches designed to enhance CAR-T cell therapy of solid tumours and assess their translational potential. Methods: A narrative review of recent pre-clinical translational studies was conducted, focussing on biomaterial platforms developed to improve CAR-T cell delivery, persistence, functionality, safety control, and manufacturing efficiency in solid-tumour settings. Approaches were analysed according to their mechanisms of action, therapeutic benefits, and stage of translational readiness. Results: Biomaterial strategies, including nanoparticles, injectable and implantable hydrogels, scaffolds, and hybrid delivery systems, have improved CAR-T infiltration, survival, and therapeutic efficacy in several solid-tumour models. Localised delivery of cytokines and other immunomodulatory cues enabled improved spatio-temporal control of CAR-T activation, reducing systemic toxicity, and increasing persistence. Additional applications include amplified ex vivo CAR-T expansion and support for non-viral or in vivo CAR-T generation. However, increased material complexity was frequently associated with challenges in scalability, regulatory approval, and long-term safety. Conclusions: Biomaterial-enabled approaches offer a versatile toolkit to address key biological and translational barriers limiting CAR-T cell therapy of solid tumours. Strategies based on clinically familiar materials and simplified designs appear most suitable for near-term clinical translation, emphasising the need to balance engineering innovation with safety, scalability, and integration into existing clinical workflows. Full article

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. Full article

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and exhibits considerable biological heterogeneity in both molecular and clinical characteristics. The diverse molecular alterations and clinical manifestations of HCC indicate substantial heterogeneity across patient subgroups. This study aimed to identify novel therapeutic targets and predictive biomarkers associated with HCC using an integrative bioinformatics approach. High-throughput genomic datasets were obtained from the UCSC Xena browser to retrieve mRNA HTSeq-count data from the TCGA-HCC cohort. Gene co-expression network (GCN), protein–protein interaction network (PPIN), and enrichment analyses were performed to identify key dysregulated genes and their biological significance. Integrated network analyses identified three dysregulated hub genes, namely CXCR2, TLR2, and TLR4. Genomic alterations in these genes were further evaluated across tumor samples in the TCGA-HCC cohort. Kaplan–Meier (KM) survival analysis demonstrated that lower CXCR2 mRNA expression was significantly associated with poorer overall survival (OS) and recurrence-free survival (RFS). Furthermore, TIMER and UALCAN analyses revealed significant associations between CXCR2 expression and tumor purity, as well as immune cell infiltration levels, including T cells, macrophages, dendritic cells (DCs), and neutrophils. These findings suggest that CXCR2 is significantly associated with the immune microenvironment of HCC and represents a potential prognostic biomarker whose biological role warrants further mechanistic investigation. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Cellular senescence contributes to chronic inflammation, yet key senescence-associated regulators in RA remain unclear. This study aimed to identify RA senescence-related signatures and their roles. Using GSE89408 as the training cohort, we screened hub genes by intersecting differentially expressed and senescence-related genes via WGCNA and three machine learning algorithms, with GSE55457 for external validation. Immune infiltration, regulatory network, subtyping and drug prediction were analyzed. Clinical and in vitro assays validated RIPK2 expression and function in the macrophage senescence-like phenotype, with preliminary signaling exploration. Three senescence-related hub genes (TNFAIP6, SLC2A3, RIPK2) were identified. The derived nomogram showed robust diagnostic performance (AUC = 0.988). Hub genes correlated strongly with myeloid cells, especially macrophages. Two immunologically distinct RA subtypes were identified. RIPK2 was upregulated in clinical samples; its inhibition attenuated LPS-induced macrophage senescence-like changes and inflammation. Preliminary data suggested RIPK2 may act via the NF-κB pathway. This study identifies RA senescence-associated signatures, revealing RIPK2 linking innate immunity to macrophage senescence-like changes, offering novel insights into pathogenesis and supporting it as a candidate biomarker and therapeutic target. Full article

Immunotherapy can reduce treatment-related side effects but shows limited efficacy in “cold tumors,” whose immunosuppressive tumor immune microenvironment is characterized by abundant M2 macrophages and poor T cell infiltration. Because biopsy-based qualitative assessment of the tumor microenvironment is invasive and conventional imaging lacks functional information, this study aimed to develop an M2 macrophage-targeted theranostic agent enabling non-invasive photoacoustic (PA) imaging and pH-triggered cytotoxicity. A pullulan-based nanogel conjugated with mannose and near-infrared dye (IR-820) was further functionalized with the pH-responsive doxorubicin (DOX) prodrug, Aldoxorubicin, to develop Pullulan-mannose-IR820-Aldoxorubicin (PMID) nanogel. PMID was successfully synthesized, and the resulting self-assembled nanogels (<100 nm) exhibited a highly negative ζ-potential, near-infrared absorption peaks at 780 and 850 nm, and PA contrast comparable to IR-820 at 850 nm excitation. Dialysis studies demonstrated suppressed drug release at neutral pH (~20%) but accelerated release under acidic conditions, reaching ~80% within 48 h at pH 5.5, consistent with hydrazone hydrolysis and supporting tumor/lysosome-activated delivery. In RAW264.7 macrophages, PMID nanogel showed preferential uptake by M2-poralized versus M1-polarized macrophages, outperforming non-mannosylated PID nanogel and IR-820, and produced the strongest PA signal in M2 macrophage pellets. PMID nanogel also induced the highest concentration-dependent cytotoxicity in M2 macrophages, and microscopy indicated lysosomal accumulation of the nanogel with partial nuclear localization of released DOX. These findings support the use of PMID nanogel as M2 macrophage-targeted PA contrast agents and pH-responsive drug carriers with the potential to deplete immunosuppressive macrophages, modulate cold tumor microenvironments, and improve precision cancer theranostics. Full article