Cancer immunotherapy represents a promising strategy, however, its efficacy is often hindered by high tumor interstitial fluid pressure (TIFP) due to fluid retention, and strong solid stress (SS) caused by the excessive proliferation of cancer-associated fibroblasts (CAFs). These factors limit the infiltration of immune cells into the deeper layers of tumors, thereby reducing the efficacy of immunotherapy. In this study, we designed an innovative AgNbO3/Pt@HA (ANPH) Schottky heterojunction system to induce ultrasound (US)-triggered piezocatalytic reactions for cancer therapy, which catalyze the water decomposition in the tumor interstitial fluid to produce H2, therefore, resulting in a 48.16 % reduction in TIFP. Furthermore, the reactive oxygen species (ROS) generated by the system eliminated 59.4 % of CAFs, reducing the tumor extracellular matrix and SS by 44.07 %. This reduction facilitated a 3.95-fold and 3-fold increase in quantities of intratumoral CD8+ and CD4+ T cells, respectively, and transformed "cold tumors" into "hot tumors" to activate systemic immune responses. The growth of primary, distal, and metastatic tumors was significantly inhibited. This study demonstrates effective reductions in intratumoral TIFP and SS, promoting immune cell infiltration and thereby enhancing the efficacy of immunotherapy through US-triggered piezocatalytic reactions, which establishes a new paradigm of the application of nanocatalytic medicine.

68Ga-DOTA-FAPI-04 is a new positron imaging agent, and its application in bone metastasis has been limited. The purpose of this retrospective study was to compare the diagnostic ability of 68Ga-DOTA-FAPI-04 PET/CT and 18F-FDG PET/CT to detect bone metastases in patients with different types of cancer.

A total of 293 patients with pathologically confirmed primary malignancies were examined with 68Ga-DOTA-FAPI-04 PET/CT and 18F-FDG PET/CT within one week. Using pathological examination or follow-up CT or MRI scan as the gold standard, the diagnostic efficacy of the two methods in differentiating bone metastases was compared (p < 0.05, with statistical significance). The maximum standard uptake value (SUVmax) of the two methods for different types of bone metastasis was further compared. The SUVmax was used to compare the differences between the two methods in detecting bone metastases in different tumor types and different sites.

A total of 48 patients were diagnosed with bone metastasis, and 245 patients without bone metastasis. There were 376 bone metastases and 243 benign bone lesions. 68Ga-DOTA-FAPI-04 PET/CT and 18F-FDG PET/CT detected 376 and 228 metastases, respectively. Sensitivity, specificity, positive and negative predictive value (PPV and NPV) and accuracy of 68Ga-DOTA-FAPI-04 PET/CT and 18F-FDG PET/CT were 100.0 % vs 60.6 %, 93.8 % vs 99.2 %, 96.2 % vs 99.2 %, 100.0 % vs 62.0 % and 97.6 % vs 75.8 %, respectively. Compared with 18F-FDG, 68Ga-DOTA-FAPI-04 uptake was significantly increased in both benign bone lesions and metastases (p = 0.001). The uptake of 68Ga-DOTA-FAPI-04 for osteoblastic metastasis was also significantly higher than that of 18F-FDG (p < 0.001). In bone metastasis of lung cancer and gastric cancer, 68Ga-DOTA-FAPI-04 uptake was higher than that of 18F-FDG PET/CT (p < 0.05). Using SUVmax = 4.1 and SUVmax = 6.2 as the cutoff value by 68Ga-DOTA-FAPI-04 PET/CT and 18F-FDG PET/CT, it was possible to predict the occurrence of metastases (AUC = 0.817,95 % CI: 0.791-0.923 vs AUC =0.751,95%CI:0.626-0.875).

68Ga-DOTA-FAPI-04 as a novel imaging agent, can detect more bone metastases and has a higher tracer uptake level than 18F-FDG. Especially for lung and gastric cancer, 68Ga-DOTA-FAPI-04 PET/CT may be a more reliable means to detect bone metastases.

Fibroblasts are important components in the tumor microenvironment and can affect tumor progression and metastasis. However, the roles of genetic variants of the fibroblast-related genes (FRGs) in the prognosis of non-small-cell lung cancer (NSCLC) patients have not been reported. Therefore, we investigated the associations between 26,544 single nucleotide polymorphisms (SNPs) in 291 FRGs and survival of NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In Cox regression multivariable analysis, we found that 661 SNPs were associated with NSCLC overall survival (OS). Then we validated these SNPs in another independent replication dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. Finally, we identified two independent SNPs (i.e., FER rs7716388 A>G and SULF1 rs11785839 G>C) that remained significantly associated with NSCLC survival with hazards ratios (HRs) of 0.87 (95% confidence interval [CI] = 0.77-0.98, p = 0.018) and 0.88 (95% CI = 0.79-0.99, p = 0.033), respectively. Combined analysis for these two SNPs showed that the number of protective alleles was associated with better OS and disease-specific survival. Expression quantitative trait loci analysis indicated that the FER rs7716388 G allele was associated with the up-regulation of FER mRNA expression levels in lung tissue. Our results indicated that these two functional SNPs in the FRGs may be prognostic biomarkers for the prognosis of NSCLC patients, and the possible mechanism may be through modulating the expression of their corresponding genes.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a poor prognosis. A prominent feature of PDAC is the rich and dense stroma present in the tumor microenvironment (TME), which significantly hinders drug penetration. Cancer-associated fibroblasts (CAFs), activated fibroblasts originating from various cell sources, including pancreatic stellate cells (PSCs) and mesenchymal stem cells (MSCs), play a critical role in PDAC progression and TME formation. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules that are frequently involved in tumorigenesis and progression, exhibiting either oncolytic or oncogenic activity. Increasing evidence suggests that aberrant expression of miRNAs can mediate interactions between cancer cells and CAFs, thereby providing novel therapeutic targets for PDAC treatment. In this review, we will focus on the potential roles of miRNAs that target CAFs or CAFs-derived exosomes in PDAC progression, highlighting the feasibility of therapeutic strategies aimed at restoring aberrantly expressed miRNAs associated with CAFs, offering new pathways for the clinical management of PDAC.

Esophageal squamous cell carcinoma (ESCC) is a common and aggressive subtype of esophageal cancer. This research investigates the functions of cancer-associated fibroblasts (CAFs) in the malignant phenotype of ESCC and probes the underpinning mechanism. Key CAF-associated proteins in ESCC were identified using bioinformatics analyses. ESCC cell lines were co-cultured with CAFs, followed by the addition of neutralizing antibodies against WNT family member 5A (WNT5A) (Anti-WNT5A; AW) and frizzled class receptor 5 (FZD5) (Anti-FZD5; AF), or a human recombinant protein of WNT5A (rWNT5A; rW). The effects of CAF stimulation and the neutralizing or recombinant proteins on the growth and dissemination of ESCC cells were investigated. In addition, ESCC cells were transplanted into nude mice for in vivo assessment of tumor growth and metastasis. WNT5A was identified as a CAF-associated protein linked to poor prognosis in ESCC. Co-culturing with CAFs augmented proliferation, mobility, and apoptosis resistance of ESCC cells. These effects were negated by the AW or AF but restored by rW. WNT5A interacted with FZD5 to activate the WNT signaling in ESCC cells. The rW treatment also enhanced tumorigenesis and metastasis of xenograft tumors in nude mice, with these effects diminished by AW or AF treatment. This study suggests that CAFs promote growth and dissemination of ESCC cell primarily through the secretion of WNT5A.

High-throughput screening (HTS) three-dimensional (3D) tumor models are a promising approach for cancer drug discovery, as they more accurately replicate in vivo cell behavior than two-dimensional (2D) models. However, assessing and comparing current 3D models for drug efficacy remains essential, given the significant influence of cellular conditions on treatment response. To develop in vivo mimicking 3D models, we evaluated two HTS 3D models established in 96-well plates with 3D polycaprolactone (PCL) scaffolds fabricated using two distinct methods, resulting in scaffolds with either homogenous or non-homogenous fiber networks. These models, based on human HeLa cervical cancer cells and cancer-associated fibroblasts (CAFs) cultured as mono- or co-cultures within the 3D scaffolds, revealed that anticancer drug paclitaxel (PTX) exhibited consistently higher inhibitory concentration 50 (IC50) in 3D (≥ 1000 nM) compared to 2D (≥ 100 nM), indicating reduced toxicity on cells cultured in 3D. Interestingly, the toxicity of PTX was significantly lower on mini-tumors in non-homogenous 3D (IC50: 600 or 1000 nM) than in homogenous 3D cultures (IC50 exceeding 1000 nM). Microscopic studies revealed that the non-homogenous scaffolds closely resemble the tumor collagen network than their homogeneous counterpart. Both 3D scaffolds offer optimal pore size, facilitating efficient cell infiltration into the depth of 58.1 ± 1.2 µm (homogenous) and 86.4 ± 9.8 µm (non-homogenous) within 3D cultures. Cells cultured in the 3D non-homogenous systems exhibited drug treatment responses closer to in vivo conditions, highlighting the role of scaffold structure and design on cellular response to drug treatment. The PCL-based 3D models provide a robust, tunable, and efficient approach for the HTS of anti-cancer drugs compared to conventional 2D systems.

Induction chemoimmunotherapy (ICIT) has emerged as a potential treatment option for resectable hypopharyngeal cancer (HPC), while its effectiveness remains limited to a significant portion of HPC cases, and a major challenge behind lies in the lack of reliable molecular markers to identify treatment-resistant patients. In this study, we analyzed biopsy samples of HPC patients collected before and after ICIT, classifying them based on treatment response. By investigating the tumor microenvironment (TME) at the single-cell level, we demonstrated that the heterogeneity within the TME is closely linked to different treatment outcomes. Specially, a strong treatment response correlated with a subpopulation of cancer-associated fibroblasts (CAFs). Additionally, we identified that the S100A2 gene is highly expressed in tumor cells and appears to influence ICIT efficacy. Using bulk RNA sequencing, we estimated cell composition and validated these observations at the protein level. Our research provides a novel approach for identifying genes and cell populations that predict treatment responses in HPC, potentially enabling the timely identification of treatment-resistant patients. This could increase the likelihood of preserving laryngeal function and optimizing treatment strategies.

This study aimed to identify the key cell types and their interactions in gynecological oncology of breast cancer, cervical cancer, and ovarian cancer. Single-cell RNA sequencing was performed on tumor samples of gynecological oncology from the GEO database. Cell types were identified using SingleR and cell composition was analyzed to understand the tumor microenvironment (TME). CellChat was used to analyze cell interactions, and pseudotemporal analysis was conducted on cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) to understand their differentiation status. Four CAF subtypes were identified: iCAF, myCAF, proCAF, and matCAF. The iCAF subpopulation secreted COL1A1 and promoted tumor cell migration, while myCAF was involved in angiogenesis. The matCAF subpopulation was present throughout tumor development. TAMs were found to promote angiogenesis through the VEGFA_VEGFR2 signaling pathway. CAFs and TAMs play pivotal roles in tumor progression through their interactions and signaling pathways.

This study evaluated 18F-aluminum fluoride fibroblast activation protein inhibitor 42 (18F-AlF-FAPI-42) PET/computed tomography (CT) imaging characteristics in primary liver cancer (PLC) and analyzed detection rate determinants.

Fifty-three untreated patients (76 lesions) with suspected PLC [hepatocellular carcinoma (HCC) or non-HCC subtypes] underwent 18F-AlF-FAPI-42 PET/CT. Maximum standardized uptake value (SUV max ) of lesions and mean SUV of adjacent normal liver tissue were measured to calculate target-to-background ratio (TBR). Patients were stratified by pathology, cirrhosis status, lesion size [small (3 cm), nodular (3-5 cm), massive (>5 cm)], lesion number, and alpha-fetoprotein (AFP).

Overall positivity rate was 86.8% (66/76 lesions). Non-HCC lesions showed significantly higher SUV max (15.6 vs. 10.3; P < 0.001) and TBR (12.6 vs. 3.9; P < 0.001) than HCC. Lesion size correlated with SUV max ( r = 0.54) and TBR ( r = 0.37) (both P < 0.001). HCC demonstrated lower detection than non-HCC (80.6 vs. 100%; P = 0.018), while cirrhotic patients showed reduced detection vs. noncirrhotic (80 vs. 96.8%; P = 0.034). Detection rates increased with lesion size: 72.0% (small), 80.0% (nodular), and 100% (massive) ( P = 0.004). Lesion number and AFP levels showed no significant impact. Subgroup analysis confirmed lesion size and pathological type as independent predictors ( P < 0.05), while cirrhosis showed no independent effect ( P > 0.05).

18F-AlF-FAPI-42 PET/CT demonstrates high sensitivity for PLC, particularly for non-HCC subtypes and larger lesions. While smaller HCCs show reduced detection, cirrhosis doesn't significantly impair diagnostic performance, supporting its clinical utility in cirrhotic populations.

Ovarian cancer, ranking fifth in cancer mortality, presents a significant therapeutic challenge. The immunomodulatory functions of CD38in epithelial ovarian cancer (EOC) and its influence on the tumor microenvironment (TME) remain poorly understood.

Public datasets, RT-qPCR and immunohistochemistry (IHC) were used to analyze CD38 expression and clinicopathological features in EOC. Gene manipulation techniques were employed to elucidate its functions, while integrated IHC and bioinformatics were conducted to assess its involvement in immune/stromal infiltration. Immune-related functions of CD38 were explored using GO, KEGG analysis and TIP database. TIDE algorithm was employed to predict the correlation between CD38 and immune checkpoint blocking responsiveness. CD38 inhibitor efficacy was evaluated in an EOC mouse model, with flow cytometry monitoring cellular changes. The involvement of CD38 in the PI3K-AKT and IL-6 signaling pathways was evaluated using RT-qPCR, western blot, and publicly datasets.

CD38 is significantly upregulated in EOC, influencing the cell proliferation and metastasis. It regulates the PI3K-AKT and IL-6 signaling pathways, thereby increasing tumor malignancy. CD38 is also upregulated in immune and stromal cells, affecting TME remodeling by facilitating immune cell and CAF infiltration, impeding T cell recognition of tumor cells, and enhancing CAF-tumor cell communication. Additionally, CD38 correlates with multiple immune checkpoint molecules. Notably, CD38 inhibitor therapy inhibited effectively EOC progression and modulates immune responses.

Elevated CD38 expression is associated with EOC progression, TME remodeling, and immune response modulation. Thus, CD38 could be a promising target for ovarian cancer immunotherapy.

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, we provide a comprehensive view of the NSCLC TME, examining its components and highlighting distinct archetypes characterized by spatial niches within and surrounding tumour nests, which form complex neighbourhoods. Next, we explore the interactions within these components, focusing on how inflammation and immunosuppression shape the dynamics of the NSCLC TME. We also address the emerging influences of patient-related factors, such as ageing, sex and health disparities, on the NSCLC-TME crosstalk. Finally, we discuss how various therapeutic strategies interact with and are influenced by the TME in NSCLC. Overall, we emphasize the interconnectedness of these elements and how they influence therapeutic outcomes and tumour progression.

Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer, with a poor prognosis driven by therapy resistance and a propensity for recurrence. Tumor microenvironment (TME)-associated fibrosis accelerates disease progression by fostering immune evasion. Neuropilin-1 (NRP1), a key mediator in fibrotic signaling and cancer biology, has been implicated in these processes. However, the genetic correlation between fibrogenesis and ccRCC remains largely unexplored, necessitating a focused analysis of fibrogenesis-related genes (FRGs) to identify novel prognostic markers and therapeutic strategies.

This study utilized an integrative bioinformatics framework to identify prognosis-associated fibrogenesis-related genes (pFRGs) and applied non-negative matrix factorization (NMF) to stratify ccRCC patients based on fibrotic signatures. A machine learning-derived prognostic model was developed to categorize patients into high-risk and low-risk groups, with tumor microenvironment (TME) features analyzed across these subgroups. The pro-tumorigenic role of NRP1 via the TGF-β/SMAD signaling pathway was validated in vitro and in vivo.

Twelve pFRGs were identified, with elevated expression correlating with reduced survival. NMF revealed two ccRCC subtypes with different fibrotic and immune profiles. The high-fibrosis subtype showed worse survival and a pro-tumorigenic TME. The risk model demonstrated robust predictive performance (AUCs: 0.738, 0.731, 0.711 for 1-, 2-, and 3-year survival). High-risk patients, marked by immune dysfunction, exhibited worse survival but greater immunotherapy sensitivity. Among the pFRGs, NRP1 was upregulated in ccRCC, and paradoxically associated with favorable prognosis in TCGA, primarily due to stromal enrichment. In vitro and in vivo experiments confirmed that NRP1 promotes ccRCC proliferation, migration, and invasion by enhancing TGF-β/SMAD-driven epithelial-mesenchymal transition (EMT).

Fibrosis is a critical driver of ccRCC progression, linking fibrogenesis-related genes to poor prognosis, immune suppression, and tumor aggressiveness. NRP1 was identified as a central regulator of fibrosis-induced tumor progression through the TGF-β/SMAD signaling pathway. Combining NRP1 inhibition with anti-fibrotic therapies presents a potential strategy for enhancing therapeutic outcomes in ccRCC.

Glutamine (Gln), a critical metabolic substrate, fuels the uncontrolled proliferation of cancer cells. Cancer-associated fibroblasts (CAFs), essential components of the tumor microenvironment, facilitate tumor progression by supplying Gln to cancer cells and driving drug resistance through metabolic reprogramming. This review highlights the key processes of Gln uptake, transport, and catabolism and explores the metabolic crosstalk between CAFs and cancer cells. It also examines the roles of major oncogenic regulators-c-Myc, mTORC, KRAS, p53, and HIF-in controlling Gln metabolism and shaping therapeutic resistance. Current pharmacological approaches targeting Gln metabolism, including enzyme inhibitors and transporter blockers, are discussed alongside emerging therapeutic strategies and ongoing clinical trials. Lastly, we underscore the importance of integrating advanced technologies like artificial intelligence and spatial omics to refine treatment targeting and develop more effective, personalized therapeutic interventions.

External beam radiation therapy (RT) is a cornerstone of modern cancer management, being utilized in both curative and palliative settings due to its safety, efficacy, and widespread availability. A primary biological effect of RT is DNA damage, which leads to significant cytostatic and cytotoxic effects. Importantly, malignant cells possess a limited capacity for DNA repair compared to normal cells, and when combined with irradiation techniques that minimize damage to healthy tissues, this creates an advantageous therapeutic window. However, the clinical effectiveness of RT also appears to involve both direct and indirect interactions between RT and non-transformed components of the tumoral ecosystem, particularly immune cells. In this review, we describe the molecular and cellular mechanisms by which irradiated cancer cells modify the immunological tumor microenvironment and how such changes ultimately impact tumor growth.

Atherosclerosis is a complex process involving various cells and molecules within the atherosclerotic plaque. Recent evidence suggests that plaque-associated fibroblasts (PAFs), also known as atherosclerosis-associated fibroblasts (AAFs), might play a significant role in the development and progression of the disease. The microenvironment of the atherosclerotic plaque, resembling the tumor microenvironment (TME), includes various cellular populations like plaque-associated macrophages (PAMs), plaque-associated neutrophils (PANs), vascular smooth muscle cells (VSMCs), myeloid-derived suppressor cells (MDSCs), and PAFs. Similar to cancer-associated fibroblasts (CAFs) in tumors, PAFs exhibits a wide range of characteristics and functions. Their interactions with endothelial cells, smooth muscle cells, and other stromal cells, including adventitial fibroblast precursors, significantly influence atherosclerosis progression. Moreover, the ability of PAFs to express various markers such as alpha-SMA, Desmin, VEGF, and GFAP, highlights their diverse origins from different precursor cells, including vascular smooth muscle cells, endothelial cells, glial cells of the enteric nervous system, adventitial fibroblast precursors, as well as resident and circulating fibrocytes. This article explores the molecular interactions between PAFs, cells associated with atherosclerosis, and other stromal cells. It further examines the role of PAFs in the development and progression of atherosclerosis, and compares their features with those of CAFs. The research suggests that studying tumor-associated fibroblasts can help understand fibroblast subpopulations in atherosclerotic plaque. Identifying specific subpopulations could provide new insight into atherosclerosis complexity and lead to the development of innovative drugs for medical intervention.

Cancer-associated fibroblasts (CAFs) are a multifaceted cell population essential for shaping the tumor microenvironment (TME) and influencing therapy responses. Characterizing the spatial organization and interactions of CAFs within complex tissue environments provides critical insights into tumor biology and immunobiology. In this study, through integrative analyses of over 14 million cells from 10 cancer types across 7 spatial transcriptomics and proteomics platforms, we discover, validate, and characterize four distinct spatial CAF subtypes. These subtypes are conserved across cancer types and independent of spatial omics platforms. Notably, they exhibit distinct spatial organizational patterns, neighboring cell compositions, interaction networks, and transcriptomic profiles. Their abundance and composition vary across tissues, shaping TME characteristics, such as levels, distribution, and state composition of tumor-infiltrating immune cells, tumor immune phenotypes, and patient survival. This study enriches our understanding of CAF spatial heterogeneity in cancer and paves the way for novel approaches to target and modulate CAFs.

This study investigates key microscopic regions involved in colorectal cancer liver metastasis (CRLM), focusing on the crucial role of cancer-associated fibroblasts (CAFs) in promoting tumor progression and providing molecular- and metabolism-level insights for its diagnosis and treatment using multi-omics. We followed 12 fresh surgical samples from 2 untreated CRLM patients. Among these, 4 samples were used for spatial transcriptomics (ST), 4 for spatial metabolomics, and 4 for single-cell RNA sequencing (scRNA-seq). Additionally, 92 frozen tissue samples from 40 patients were collected. Seven patients were used for immunofluorescence and RT-qPCR, while 33 patients were used for untargeted metabolomics. ST revealed that the spatial regions of CRLM consists of 7 major components, with fibroblast-dominated regions being the most prominent. These regions are characterized by diverse cell-cell interactions, and immunosuppressive and tumor growth-promoting environments. scRNA-seq identified that SPP1+ fibroblasts interact with CD44+ tumor cells, as confirmed through immunofluorescence. Spatial metabolomics revealed suberic acid and tetraethylene glycol as specific metabolic components of this structure, which was further validated by untargeted metabolomics. In conclusion, an SPP1+ fibroblast-rich spatial region with metabolic reprogramming capabilities and immunosuppressive properties was identified in CRLM, which potentially facilitates metastatic outgrowth through interactions with tumor cells.

C-X-C motif chemokine ligand 13 (CXCL13) is a crucial chemokine for the recruitment of immune cells and the formation of tertiary lymphoid structure (TLS) in the tumor microenvironment. However, the relationship between CXCL13 and immune infiltration in cutaneous squamous cell carcinoma (cSCC) remains unclear.

We aimed to investigate the expression of CXCL13 and explore its association with immune activation and TLS in cSCC.

A total of 63 cSCC patients were involved in the present study. Hematoxylin and eosin staining was used for pathological examination of cSCC. Bioinformatics analyses and immunohistochemical staining were employed to access the expression of CXCL13 and TLS states. Public single cell RNA-sequencing atlas of skin disorders and multiplex immunofluorescence were used to explore CXCL13-producing cells.

Utilizing the public database and our clinical cohort, we observed robust CXCL13 expression in cSCC tissues and a significant correlation with immune activation. Higher expression levels of CXCL13 were associated with lower histopathological grades and increased TLS formation. Furthermore, we confirmed that T cells and fibroblasts were the predominant cell types of CXCL13 secretion in cSCC.

CXCL13 is up-regulated in cSCC, which shows a significant positive correlation with immune infiltration and TLS formation. Our results underscore the role of CXCL13 in shaping the cSCC microenvironment, highlighting its potential as a therapeutic target.

Hypoxia serves as a critical determinant in the advancement of various intractable pathological conditions including oncological disorders and hypovascular wounds, which may profoundly attenuate the efficacy of pharmacological interventions and substantially inhibit the physiological recovery processes. Consequently, in an effort to mitigate the inherent constraints of conventional methodologies (e.g., exogenous oxygen delivery systems), a self-powered triboelectric nanogenerator (TENG)-based algae-integrated pliable and enveloped device (TAPED) operates as a wearable system to sustain oxygen generation. The TAPED system harnesses biomechanical energy generated through natural bodily movements to energize an integrated luminescent source, enabling controlled photosynthesis for sustained, on-demand oxygen production. The incorporation of TENG technology renders TAPED self-sufficient, eliminating the necessity for external recharging, reducing device mass, and improving convenience for continuous oxygen delivery. Additionally, its body-attachable design circumvents risks associated with direct algal implantation, such as immunogenic reactions and infections. Specifically, experimental application of TAPED has exhibited significant therapeutic efficacy in diverse pathological conditions, including diabetic chronic infected wounds, breast carcinoma tumors, and lactic acid accumulation consequent to strenuous exercise-induced fatigue. Collectively, the TAPED represents an advanced therapeutic approach, which holds substantial potential for translational application within clinical contexts, particularly for enhancing patient prognosis in hypoxic diseases such as oncology and wound management.

The breast tumor microenvironment is composed of heterogeneous cell populations, including normal epithelial cells, cancer-associated fibroblasts (CAFs), and tumor cells that lead collective cell invasion. Both leader tumor cells and CAFs are known to play important roles in tumor invasion across the collagen-rich stromal boundary. However, their individual abilities to utilize their cell-intrinsic protrusions and perform force-based collagen remodeling to collectively invade remain unclear. To compare collective invasion phenotypes of leader-like tumor cells and CAFs, we embedded spheroids composed of 4T1 tumor cells or mouse tumor-derived CAF cell lines within 3D collagen gels and analyzed their invasion and collagen deformation. We found that 4T1s undergo greater invasion while generating lower collagen deformation compared with CAFs. Although force-driven collagen deformations are conventionally associated with higher cellular forces and invasion, here 4T1s specifically rely on actin-based protrusions, while CAFs rely on myosin-based contractility for collective invasion. In denser collagen, both cell types slowed their invasion, and selective pharmacological inhibitions show that Arp2/3 is required but myosin-II is dispensable for 4T1 invasion. Furthermore, depletion of CDH3 from 4T1s and DDR2 from CAFs reduces their ability to distinguish between collagen densities. For effective invasion, both cell types reorient and redistribute magnetically prealigned collagen fibers. With heterogeneous cell populations of cocultured CAFs and 4T1s, higher percentage of CAFs impeded invasion while increasing collagen fiber alignment. Overall, our findings demonstrate distinctive mechanisms of collective invasion adopted by 4T1 tumor cells and CAFs, one relying more on protrusions and the other on force-based collagen deformation. These results suggest that individually targeting cellular protrusions or contractility may not be universally applicable for all cell types or collagen densities, and a better cell-type-dependent approach could enhance effectiveness of cancer therapies.

The stroma of healthy pancreases contains various non-hematopoietic, non-endothelial mesenchymal cells. It is altered by chronic inflammation which in turn is a major contributor to the development of pancreatic adenocarcinoma (PDAC). In PDAC, the stroma plays a decisive and well-investigated role for tumor progression and therapy response. This review addresses the central role of stromal cells in the early inflammation-driven development of PDAC. It focuses on major subpopulations of pancreatic mesenchymal cells, i.e., fibroblasts, pancreatic stellate cells, and multipotent stroma cells, particularly their activation and functional alterations upon chronic inflammation including the development of different types of carcinoma-associated fibroblasts. In the second part, the current knowledge on the impact of activated stroma cells on acinar-to-ductal metaplasia and the transition to pancreatic intraepithelial neoplasia is summarized. Finally, putative strategies to target stroma cells and their signaling in early pancreatic carcinogenesis are reflected. In summary, the current data show that the activation of pancreatic stroma cells and the resulting fibrotic changes has pro- and anti-carcinogenetic effects but, overall, creates a carcinogenesis-promoting microenvironment. However, this is a dynamic process and the therapeutic targeting of specific pathways and cells requires in-depth knowledge of the molecular interplay of various cell types.

The tumor microenvironment (TME) is the combination of cells and factors that promotes tumor progression, and cancer-associated fibroblasts (CAFs) are a key component within TME. CAF originates from various stromal cells and is activated by factors such as transforming growth factor-beta (TGF-β) secreted by tumor cells, favoring chemoresistance and metastasis. Recent publications have underlined plasticity and heterogeneity and their strong contribution to the reactive stroma within the TME. Our study aimed to replicate the TME's structure by creating a 3D in vitro model of ovarian cancer (OC). By incorporating diverse tumor and stromal cells, we simulated a physiologically relevant environment for studying CAF-like cell behavior within tumor spheroids in a context-dependent manner. CAF-like cells were generated by exposing human dermal fibroblasts to OC cell line conditioned media in the presence or absence of TGF-β. Herein, we found that different stimuli induce the generation of heterogeneous populations of CAF-like cells. Notably, we observed the ability of CAF-like cells to shape the intratumoral architecture and to contribute to functional changes in tumor cell behavior. This study highlights the importance of precise assessment of CAF for potential therapeutic interventions and further provides a reliable model for investigating novel therapeutic targets in OC.

Cachexia is a prevalent multifactorial syndrome characterized by a substantial decrease in food intake, which results from processes such as proteolysis, lipolysis, inflammatory activation, and autophagy, ultimately leading to weight loss. In cancer patients, this condition is referred to as cancer-related cachexia (CRC) and affects over 50% of this population. A comprehensive understanding of the intricate interactions between tumors and the host organism is essential for the development of effective treatments for tumor cachexia. This review aims to elucidate the role of the tumor microenvironment (TME) in the pathogenesis of tumor-associated cachexia and to summarize the current evidence supporting treatment modalities that target the TME.

Colorectal cancer (CRC) is the second most common malignant tumor in the world. With its increasing incidence and younger age trend, its impact on human health has been paid more and more attention. Currently, we have a variety of chemotherapy drugs that can be used to treat colorectal cancer. However, the drug resistance of colorectal cancer has become a significant factor affecting its cure rate. Some studies have reported that exosomes are related to the occurrence of drug resistance. However, the exact mechanism is not precise. Therefore, we focused on the role of cancer associated-fibroblast-derived (CAFs-derived) exosomes in colorectal progression. It was found that cancer cells transmit information through exosome interaction and induce chemotherapy resistance by promoting epithelial-mesenchymal transition (EMT), up-regulating the Wnt/β-catenin signaling pathway, transforming growth factor-β1 (TGF-β1) pathway, promoting angiogenesis and other possible molecular mechanisms. In addition, in terms of clinical significance and therapeutic strategies, we explore the clinical relevance of CAFs-derived exosomes in colorectal cancer patients and their potential as potential biomarkers for predicting chemotherapy response. We also provide a new possible direction for overcoming chemotherapy resistance in colorectal cancer by targeting CAFs-derived exosomes.

The interplay between cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) mediates progress, metastasis, and therapy resistance. However, strategy of targeting ECM remodeling to enhance chemosensitivity in ovarian cancer remains elusive. Here, a 22-gene matrisome signature predicts chemotherapy response and survival in ovarian cancer. The dense, collagen-rich ECM secreted by CAFs harbors more M2 tumor-associated macrophages (TAMs) than the looser ECM based on single cell RNA-seq (scRNA-seq) of ovarian cancer, suggesting the promising approach of targeting collagen to remodel ECM. An integrated analysis identifies collagen type I alpha 1 chain (COL1A1) as a major component of the ECM that contributes to chemoresistance and poor prognosis, highlighting its potential as a therapeutic target. Halofuginone (HF), a clinically active derivative of febrifugine, is identified as a COL1A1-targeting natural compound by screening the Encyclopedia of Traditional Chinese Medicine (ETCM). Mechanistically, HF inhibits COL1A1 production via the mTOR-eIF2α-ATF4 axis in CAFs. Notably, HF disrupts collagen deposition and promotes CD8+ T cell infiltration, partially via M2-M1 macrophage polarization to enhance chemosensitivity. Overall, the findings suggest that HF combined with chemotherapy is a promising and effective treatment for ovarian cancer.

Cancer associated fibroblasts (CAFs) play a critically important role in facilitating tumour cell invasion during metastasis. They also modulate local biophysical features of the tumour microenvironment through the formation of fibrotic foci, which have been correlated with breast cancer aggression. However, the impact of the evolving three-dimensional biophysical tumour microenvironment on CAF function remains undefined. Here, by isolating CAFs from primary human triple-negative breast cancer tissue at the time of surgery, we find that their ability to remodel the local microenvironment and invade into a three-dimensional matrix correlates with disease state. We then engineered culture models to systematically deconstruct and recreate mechanical tissue features of early breast cancer fibrotic foci; and demonstrate that invasion is mechanically-activated only in CAFs from patients with no detectable pre-existing metastases, but is independent of mechanical cues in CAFs isolated from patients with later-stage axillary lymph node metastases. By comparing the differential transcriptional response of these cells to microenvironmental tissue stiffness, we identify the aryl hydrocarbon receptor (AhR) as being significantly upregulated in invasive sub-populations of both mechanically-activated and mechanically-insensitive CAFs. Increasing AhR expression in CAFs induced invasion, while suppressing AhR significantly reduced invasion in both mechanically-activated and mechanically-insensitive CAF populations, even on stiffnesses that recapitulate late-stage disease. This work therefore uses mechanobiological analyses to identify AhR as a mediator of CAF invasion, providing a potential stratification marker to identify those patients who might respond to future mechanics-based prophylactic therapies, and provides a targetable mechanism to limit CAF-associated metastatic disease progression in triple-negative breast cancer patients. STATEMENT OF SIGNIFICANCE: By designing a mechanically-tunable tissue-engineered model of fibroblastic foci, and using this to culture patient-derived cancer-associated fibroblasts, we demonstrate that these cells are differentially mechanosensitive, depending on disease stage of the patient. While comparing transcriptomic profiles of patient-derived cells produces too many pathways to screen, identifying the pathways activated by local tissue mechanics that were common across each patient allowed us to identify a specific target to limit fibroblast invasion. This broad discovery strategy may be useful across a variety of biomaterials-based tissue engineered models; and these specific findings suggest (1) a strategy to identify patients who might respond to CAF- or matrix-targeting therapies, and (2) a specific actionable target to limit CAF-associated metastatic disease progression.

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, with poor prognosis for metastatic cases. We demonstrated previously that cSCC cells in culture express C1r and C1s components of the complement C1qr2s2 complex but not C1q. In this study, significantly higher mRNA levels of C1QA, C1QB, and C1QC variants 1 and 2 were found in cSCC tumors than in normal skin. Analysis of single-cell RNA-sequencing data of cSCC revealed expression of mRNAs for C1QA, C1QB, and C1QC in macrophages and activated fibroblasts. C1q staining was detected on the surface of cSCC tumor cells, in peritumoral and intratumoral macrophages, and in peritumoral activated fibroblasts using immunohistochemistry and multiplexed immunofluorescence. Expression was higher in cSCCs than in normal skin, actinic keratoses, and cSCC in situ. C1q production was induced in 3-dimensional spheroid cocultures of cSCC cells, fibroblasts, and macrophages. C1q stimulated the growth of cSCC cells in culture. C1q expression was significantly more prevalent in metastatic primary cSCCs and in metastases than in non-metastatic cSCCs. High C1q expression in cSCC correlated with poor prognosis. These findings provide evidence for macrophage- and fibroblast-derived C1q in the progression of cSCC. They also suggest stromal C1q as a marker for cSCC metastasis and poor prognosis.

Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.

Each stage of tumor development is intrinsically linked to the tumor microenvironment (TME), wherein the extracellular matrix (ECM) serves as a vital and abundant component in tumor tissues. The ECM is a non-cellular, three-dimensional macromolecular network scaffold that provides structural support to cells, stores bioactive molecules, and mediates signaling pathways through specific binding to cell surface receptors. Moreover, the ECM in tumor tissues plays a crucial role in impeding drug diffusion and resisting apoptosis induced by conventional anti-cancer therapies that primarily target cancer cells. Therefore, directing attentions towards the tumor ECM can facilitate the identification of novel targets and the development of new therapies. This review aims to summarize the composition, structure, remodeling, and function of tumor ECM, its association with drug resistance, and current targeting strategies, with a specific emphasis on nanoparticles (NPs).

This study aims to systematically review and perform a meta-analysis to compare the diagnostic performance of fibroblast activation protein inhibitors (FAPI) radiopharmaceuticals and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in gynaecological cancers.

A comprehensive search of PubMed/MEDLINE and EMBASE was conducted and updated to October 25, 2024, to identify clinical studies evaluating FAPI and [18F]FDG PET/CT or PET/MR in patients with gynaecological cancer. Quality was assessed using the QUADAS-2 tool (Quality Assessment of Diagnostic Accuracy Studies). Per-lesion pooled estimates of sensitivity, specificity, positive predictive value, and negative predictive value were calculated with 95% confidence intervals.

Ten studies were included for qualitative assessment and five studies focusing on ovarian cancer were included in the meta-analysis. The detection rates of primary cervical cancer ranged from 96 to 100% for both radiopharmaceuticals. For the primary tumour in ovarian cancer, the pooled sensitivities of 68Ga-FAPI and [18F]FDG were 95% and 92%, and the pooled specificities were 81% for both radiopharmaceuticals. Nodal metastases detection was higher with 68Ga-FAPI compared with [18F]FDG in cervical cancer. Similarly, in ovarian cancer the estimated pooled sensitivities of 68Ga-FAPI and [18F]FDG were 97% and 88%, and the pooled specificities were 83% and 41%, respectively. At peritoneal metastases analysis in ovarian cancer, the pooled sensitivities of 68Ga-FAPI and [18F]FDG were 97% and 70%, and the pooled specificities were 93% and 88%, respectively. At the visual assessment of peritoneal cancer scores, such as peritoneal cancer index, 68Ga-FAPI detected a greater tumour burden compared with [18F]FDG. A comparative analysis of the PET semiquantitative parameters was also performed.

Despite limited literature data, radiopharmaceuticals based on FAPIs are a promising alternative to [18F]FDG for imaging gynaecological cancers, in particular for the detection of nodal metastases in cervical and ovarian cancers, as well as for detecting peritoneal metastases in ovarian cancers. Larger prospective studies are needed to confirm these results and promote the inclusion of FAPI radiopharmaceuticals in clinical practice.

Not applicable.

Cancer-associated fibroblasts (CAFs) are tissue residing cells within the tumor microenvironment (TME). Stromal CAFs have been shown to be associated with poor prognosis and tumor progression in several solid tumor entities. Although the molecular mechanisms are not fully understood yet, a critical role within the TME through direct interaction with the tumor cells as well as other cells has been proposed. While most studies on CAFs focus on stromal CAFs, recent reports highlight the possibility of detecting circulating CAFs (cCAFs) in the blood. In contrast to invasive tissue biopsies for stromal CAF characterization, liquid biopsy allows a minimally invasive isolation of cCAFs. Furthermore, liquid biopsy methods could enable continuous monitoring of cCAFs in cancer patients and therefore may present a novel biomarker for solid tumors. In this work, we present an overview of cCAF studies currently available and summarize the liquid biopsy techniques for cCAF isolation and detection. Moreover, the future research directions in the emerging field are highlighted and the potential applications of cCAFs as novel biomarkers for solid tumor patients discussed.

This study introduces TG-ME, an innovative computational framework that integrates transformer with graph variational autoencoder (GraphVAE) models for dissection of tumoral niches using spatial transcriptomics data and morphological images. TG-ME effectively identifies and characterizes niches in bench datasets and a high resolution NSCLC dataset. The pipeline consists in different stages that include normalization, spatial information integration, morphological feature extraction, gene expression quantification, single cell expression characterization, and tumor niche characterization. For this, TG-ME leverages advanced deep learning techniques that achieve robust clustering and profiling of niches across cancer stages. TG-ME can potentially provide insights into the spatial organization of tumor microenvironments (TME), highlighting specific niche compositions and their molecular changes along cancer progression. TG-ME is a promising tool for guiding personalized treatment strategies by uncovering microenvironmental signatures associated with disease prognosis and therapeutic outcomes.

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

Cancer-associated fibroblasts (CAFs) are integral components of the tumor microenvironment playing key roles in tumor progression, metastasis, and therapeutic resistance. However, challenges persist in understanding their heterogeneity, origin, and functional diversity. One major obstacle is the lack of standardized naming conventions for CAF subpopulations, with current systems failing to capture their full complexity. Additionally, the identification of CAFs is hindered by the absence of specific biomarkers, limiting the precision of diagnostic and therapeutic strategies. In vitro culture conditions often fail to maintain the in vivo characteristics of CAFs, which complicates their study and the translation of findings to clinical practice. Although current detection methods, such as antibodies, mRNA probes, and single-cell transcriptomics, offer insights into CAF biology, they lack standardization and fail to provide reliable quantitative measures. Furthermore, the dynamic interactions between CAFs, tumor cells, and immune cells within the TME remain insufficiently understood, and the role of CAFs in immune evasion and therapy resistance is an area of ongoing research. Understanding how CAFs influence drug resistance and the immune response is essential for developing more effective cancer therapies. This review aims to provide an in-depth analysis of the challenges in CAF research, propose future research directions, and emphasize the need for improved CAF-targeted therapeutic strategies. By addressing these gaps, it seeks to highlight the potential of CAFs as targets for overcoming therapeutic resistance and enhancing the efficacy of cancer treatments.

Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play an important role in tumor progression. Colon cancer cells deficient in p53 activate fibroblasts and enhance fibroblast-mediated tumor growth. Meflin is a CAF marker capable of inhibiting tumor growth. In this study, we investigated the role of Meflin in fibroblasts using human cell lines (colon cancer HCT116 and fibroblasts CCD-18Co) and clinical specimens. TP53-suppressed HCT116 (HCT116sh p53) cells cocultured with CCD-18Co cells showed significantly faster proliferation than HCT116sh control cells. In xenograft experiments, the volume of tumors induced by coinoculation with HCT116sh p53 and CCD-18Co cells was significantly larger than that induced by HCT116sh control cells co-inoculated with CCD-18Co cells. HCT116sh p53 cells increased the levels of CAF-like phenotypic markers in CCD-18Co cells. Moreover, Meflin expression was significantly reduced in CCD-18Co cells cocultured with HCT116sh p53 cells compared to that in CCD-18Co cells cocultured with HCT116sh control cells. si-RNA-mediated inhibition of Meflin activated CCD-18Co cells into tumor-promoting CAF-like cells, which significantly promoted xenograft tumor growth. Overexpression of Meflin in CCD-18Co cells using lentivirus suppressed fibroblast-mediated growth of HCT116sh p53 tumor xenografts. The expression of Meflin in CCD-18Co cells was suppressed by TGF-β and enhanced by vitamin D. These results indicate that colon cancer cells deficient in p53 suppress Meflin expression in fibroblasts, which affects tumor growth by altering the properties of tumor growth-promoting CAFs. Our results suggest that targeting Meflin in fibroblasts may be a novel therapeutic strategy for colorectal cancer.