Breast cancer remains the leading cause of cancer-related deaths among women worldwide, necessitating more effective treatment strategies. Chemotherapy combined with immunotherapy is the first-line treatment for breast cancer, but it still suffers from limited therapeutic efficiency and serious side effects, which are usually due to the poor delivery efficiency, drug resistance of tumor cells, and immunosuppressive tumor microenvironment. This study explores the development of ultrasound-responsive nanobubbles (Ce6/PTX Nbs) for targeted imaging and sonoimmunotherapy in breast cancer treatment. By integrating sonodynamic therapy (SDT), chemotherapy, and immunotherapy, the nanobubbles aim to address challenges such as poor drug delivery, systemic toxicity, and immune suppression in conventional therapies. The nanobubbles, composed of sonosensitizer chlorin e6 (Ce6)-modified phospholipid and loaded with the chemotherapeutic agent paclitaxel (PTX) enhancing drug-loading capacity, are designed to precisely target tumor sites via cyclic-RGD peptides. Upon ultrasound activation, Ce6 induces reactive oxygen species (ROS), promoting immunogenic cell death (ICD), while PTX disrupts tumor cell mitosis, enhancing the immune response. The nanobubbles' ultrasound responsiveness facilitates real-time imaging and controlled drug release, maximizing therapeutic efficacy while minimizing side effects. Key findings demonstrate that Ce6/PTX Nbs significantly reduced tumor growth in a 4T1 breast cancer model, enhanced immune activation via the cGAS-STING pathway, and increased the infiltration of CD8+ T cells in both primary and distant tumors. In combination with anti-PD-L1 checkpoint inhibitors, the treatment achieved a substantial suppression of tumor metastasis. This innovative approach offers a highly targeted, effective, and minimally toxic breast cancer treatment with potential for clinical translation due to its dual imaging and therapeutic capabilities.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of chemotherapy treatment, often resulting in the discontinuation of treatment. Paclitaxel activates peripheral macrophages, generating a neuroinflammatory response that contributes to CIPN development and maintenance. Astrocyte Elevated Gene-1 (AEG-1), also known as Metadherin or LYRIC, is a multifunctional protein that modulates macrophage activity and regulates inflammation through direct interaction with NF-κB, a transcriptional regulator of proinflammatory cytokine/chemokine (PIC) expression. We aimed to determine whether AEG-1 contributes to the development and maintenance of CIPN pathologies by using both global (AEG-1 KO) and myelocyte-specific knockout (AEG-1ΔMAC) transgenic mouse strains in an animal model of CIPN that replicates specific human clinical phenotypes. We hypothesized that inhibition of AEG1 expression in myeloid cells, such as monocytes and macrophages, would prevent the development and maintenance of CIPN. Our results showed that global AEG-1 deletion prevented the development of CIPN pathologies induced by PAC, as well as oxaliplatin (OHP). PAC treatment was found to increase AEG-1 and PIC expression in the DRGs of WT mice and in peritoneal macrophages isolated from C57BL/6J mice. However, in the absence of AEG-1 expression, PAC-induced neuroinflammation was completely halted in the DRGs of AEG-1 KO mice. This preventative phenotype and PIC expression profile was mirrored in AEG-1ΔMAC mice, which also displayed reduced NF-κB protein levels and F4/80+ macrophages trafficked to the lumbar DRGs following PAC treatment. In summary, our results are the first to demonstrate the biological role AEG-1, particularly in myeloid cells, in development of CIPN.

Positive surgical margins following radical prostatectomy significantly contribute to tumor recurrence. While systemic chemotherapy demonstrates limited efficacy in this context, local chemotherapy drug delivery systems based on nanomaterials offer promising strategies to address this issue by modifying drug release kinetics and distribution, thereby enhancing antitumor effects while minimizing the toxicities associated with systemic chemotherapy. In this study, we utilized electrospun nanofibrous mats loaded with docetaxel for sustained drug delivery. In vitro experiments demonstrated that these implantable drug-loaded nanofibrous mats effectively inhibited prostate cancer cell growth, induced cell cycle arrest, and promoted apoptosis. In animal models, these drug-loaded nanofibrous mats exhibited prominent therapeutic effects on positive surgical margins postoperatively. Importantly, docetaxel-loaded nanofibrous mats modulated the tumor immune microenvironment by suppressing M2-like macrophages, increasing the ratio between M1- and M2-like macrophages, and enhancing CD8+ T-cell infiltration. Local administration significantly reduced systemic toxicity compared to systemic chemotherapy. In summary, we developed an implantable electrospun drug-loaded nanofibrous mat for localized docetaxel delivery, which offers a prospective strategy for managing positive surgical margins after surgery.

Tumor-associated macrophages (TAMs) significantly influence tumor progression and patient responses to conventional chemotherapy. However, the interplay between anti-cancer drugs, immune responses in the tumor microenvironment, and their implications for cancer treatment remains poorly understood. This study investigates the effects of vinorelbine on M2 macrophages in lung cancer and its capacity to modulate TAMs toward an M1 phenotype. Peripheral blood mononuclear cells (PBMCs) were polarized into M2 macrophages, and subsequent phenotype alterations upon vinorelbine treatment were assessed. Additionally, we evaluated vinorelbine's impact on gene and protein expression associated with cancer progression and cell invasion in non-small-cell lung cancer (NSCLC) cells indirectly co-cultured with M2 macrophages. Notably, vinorelbine, particularly at low concentrations, reprogrammed M2 macrophages to exhibit M1-like characteristics. While M2 macrophages enhanced cancer cell invasion, vinorelbine significantly mitigated this effect. M2 macrophages led to the overexpression of numerous genes linked to tumor growth, angiogenesis, invasion, and immune suppression in NSCLC cells, increasing the BCL2/BAX ratio and promoting cellular resistance to apoptosis. The anti-tumor efficacy of vinorelbine appears to be partly attributed to the reprogramming of M2 macrophages to the M1 phenotype, suggesting that low-dose vinorelbine may optimize therapeutic outcomes while minimizing toxicity in cancer patients.

We aimed to analyze the sensitivity of patients to chemotherapy drugs and actively explore potential new intervention targets, providing an essential reference for personalized treatment.

Candidate markers with significant differential expression in macrophages were identified by analyzing gene expression at the single-cell level. A weighted gene co-expression network (WGCN) was constructed on the GSE26712 dataset to explore the modules most relevant to macrophages. Differentially expressed genes for specific markers were identified. A multi-factor regulatory network was constructed based on single-cell dataset markers screening, differentially expressed genes, and genes commonly present in WGCNA modules. Different macrophage subtypes were identified using this network. Machine learning was used to filter and predict the markers' drug sensitivity, and the potential therapeutic compounds for specific markers were screened.

We identified 14 and 17 of M1 and M2 macrophage candidate markers, respectively. In the multi-factor regulatory network of M1 macrophages, 6 out of 14 markers recognized 159 transcription factors (TFs) and 48 micro RNAs (miRNAs), whereas 13 of 17 markers recognized 191 TFs and 182 miRNAs in the multi-factor regulatory network of M2 macrophages. Filtering of the identified differentially expressed genes using random forests yielded 15 M1 and M2 macrophage-specific markers. Drug sensitivity prediction analysis and in vitro experiments revealed the close association of these markers with common chemotherapy drug sensitivity.

We identified specific M1 and M2 macrophage markers and found potential therapeutic compounds (dasatinib and afatinib) in these specific markers. These potential therapeutic compounds provide insight into the underlying mechanisms of serous ovarian cancer (OC) and inspire more effective treatment methods.

The effectiveness of immunotherapy in killing melanoma is hindered by a T-cell deficiency and the lack of tumor immunogenicity. Consequently, there is an urgent need for a platform that can further activate the immune system and boost the immune response of the host to tumors. Compared with monotherapy, combination therapy shows promise in improving treatment efficacy and response rates. This study introduces the pioneering use of a rationally designed active targeting nanoplatform to bind axitinib, paclitaxel, and verteporfin to human serum albumin (APV@HSA NPs). APV@HSA NPs have demonstrated the capability to induce dual-induced apoptosis in tumor cells through chemo- and photodynamic effects, while also enhancing immunogenic cell death and promoting dendritic cell maturation. Additionally, the platform promoted the production of CD8+ T cells and memory T cells and inhibited vascular endothelial growth factor via axitinib, facilitating the infiltration of immune effector cells and optimizing chemo-photodynamic immunotherapy. Hence, amplified chemo-photodynamic-immunological nanomedicines with excellent biocompatibility have been redesigned to inhibit the tumor microenvironment and combat the growth of primary tumor and lung metastasis. This approach initiates a series of immune responses, presenting a promising therapeutic strategy for melanoma.

Tumour-associated macrophages (TAMs) are critical components of the tumour microenvironment (TME), significantly influencing cancer progression and treatment resistance. This review aims to explore the innovative use of engineered bacteria to reprogram TAMs, enhancing their anti-tumour functions and improving therapeutic outcomes.

We conducted a systematic review following a predefined protocol. Multiple databases were searched to identify relevant studies on TAMs, their phenotypic plasticity, and the use of engineered bacteria for reprogramming. Inclusion and exclusion criteria were applied to select studies, and data were extracted using standardised forms. Data synthesis was performed to summarise the findings, focusing on the mechanisms and therapeutic benefits of using non-pathogenic bacteria to modify TAMs.

The review summarises the findings that engineered bacteria can selectively target TAMs, promoting a shift from the tumour-promoting M2 phenotype to the tumour-fighting M1 phenotype. This reprogramming enhances pro-inflammatory responses and anti-tumour activity within the TME. Evidence from various studies indicates significant tumour regression and improved immune responses following bacterial therapy.

Reprogramming TAMs using engineered bacteria presents a promising strategy for cancer therapy. This approach leverages the natural targeting abilities of bacteria to modify TAMs directly within the tumour, potentially improving patient outcomes and offering new insights into immune-based cancer treatments. Further research is needed to optimise these methods and assess their clinical applicability.

Macrophages possess the capacity to degrade extracellular matrix (ECM), but the specific roles of different cytoskeletal structures in controlling this process are incompletely understood. Here, we report that the inward flow of actin stress fibers delivers endocytosed ECM for lysosomal elimination, replenishing the pool of enzymes for extracellular ECM hydrolysis in actin-rich podosomes. Vimentin deficiency disrupted the balance between stress fibers and podosomes, impairing ECM degradation through integrin CD11b in THP-1 macrophages. In lung adenocarcinoma patient samples, M2-type macrophages exhibit a tighter podosome organization, surrounded by compact vimentin filaments, than M1-type. In vitro experiments verified that the invasion ability of A549 lung carcinoma cells was enhanced when accompanied by wild type, but not vimentin knockout M2-type THP-1, macrophages. Subcutaneous injections of macrophages and tumor cells in nude mice showed that vimentin in macrophages can reduce tumor collagen fibers. Together, our findings provide insights into the cytoskeletal dynamics governing macrophage ECM degradation.

Paclitaxel (PTX) is a first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC) but it can induce indoleamine 2,3-dioxygenase (IDO) activation, which severely lowers down its immuno-chemotherapeutic effect. To address this issue, a smart peptide hydrogelator Nap-Phe-Phe-Phe-Lys-Ser-Thr-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-T), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. Upon specific phosphorylation by pyruvate kinase M2 (PKM2), an overexpressed biomarker of NSCLC, Nap-T is gradually converted to Nap-Phe-Phe-Phe-Lys-Ser-Thr(H2PO3)-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-Tp), leading to dehydrogelation and sustained release of PTX and GDC0919 within NSCLC tissues. The released PTX exerts chemotherapy on NSCLC cells as well as immunogenic cell death induction, while GDC0919 promotes the immuno-chemotherapeutic effect of PTX through IDO inhibition. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future.

Chemoimmunotherapy is an emerging paradigm in the clinic for treating several malignant diseases, such as non-small cell lung cancer, breast cancer, and large B-cell lymphoma. However, the efficacy of this strategy is still restricted by serious adverse events and a high therapeutic termination rate, presumably due to the lack of tumor-targeted distribution of both chemotherapeutic and immunotherapeutic agents. Targeted drug delivery has the potential to address this issue. Among the most promising nanocarriers in clinical translation, liposomes have drawn great attention in cancer chemoimmunotherapy in recent years. Liposomes-enabled cancer chemoimmunotherapy has made significant progress in clinics, with impressive therapeutic outcomes. This review summarizes the latest preclinical and clinical progress in liposome-enabled cancer chemoimmunotherapy and discusses the challenges and future directions of this field.

T-cell receptor (TCR) sequencing provides a novel platform for insight into and characterization of intricate T-cell profiles, advancing the understanding of tumor immune heterogeneity. Recently, transarterial chemoembolization (TACE) combined with systemic therapy has become the recommended regimen for advanced hepatocellular carcinoma. The regulation of the immune microenvironment after TACE and its impact on tumor progression and recurrence has been a focus of research. By examining and tracking fluctuations in the TCR repertoire following combination treatment, novel perspectives on the modulation of the tumor microenvironment post-TACE and the underlying mechanisms governing tumor progression and recurrence can be gained. Clarifying the distinctive metrics and dynamic alterations of the TCR repertoire within the context of combination therapy is imperative for understanding the mechanisms of anti-tumor immunity, assessing efficacy, exploiting novel treatments, and further advancing precision oncology in the treatment of hepatocellular carcinoma. In this review, we initially summarized the fundamental characteristics of TCR repertoire and depicted immune microenvironment remodeling after TACE. Ultimately, we illustrated the prospective applications of TCR repertoires in TACE combined with systemic therapy.

In solid tumors, tumor-associated macrophages (TAMs) are one of the most numerous populations and play an important role in the processes of tumor cell invasion, metastasis, and angiogenesis. Therefore, TAMs are considered promising diagnostic and prognostic biomarkers of tumors, and many attempts have been made to influence these cells as part of antitumor therapy. There are several key principles of action on ТАМs: the inhibition of monocyte/macrophage transition; the destruction of macrophages; the reprogramming of macrophage phenotypes (polarization of M2 macrophages to M1); the stimulation of phagocytic activity of macrophages and CAR-M therapy. Despite the large number of studies in this area, to date, there are no adequate approaches using antitumor therapy based on alterations in TAM functioning that would show high efficacy when administered in a mono-regimen for the treatment of malignant neoplasms. Studies devoted to the evaluation of the efficacy of drugs acting on TAMs are characterized by a small sample and the large heterogeneity of patient groups; in addition, in such studies, chemotherapy or immunotherapy is used, which significantly complicates the evaluation of the effectiveness of the agent acting on TAMs. In this review, we attempted to systematize the evidence on attempts to influence TAMs in malignancies such as lung cancer, breast cancer, colorectal cancer, cervical cancer, prostate cancer, gastric cancer, head and neck squamous cell cancer, and soft tissue sarcomas.

Myeloid cells, including macrophages, neutrophils, dendritic cells, and myeloid-derived suppressor cells, play crucial roles in the innate immune system, contributing to immune defense, tissue homeostasis, and organ development. They have tremendous potential as therapeutic tools for diseases such as cancer and autoimmune disorders, but harnessing cell engineering strategies to enhance potency and expand applications is challenging. Recent advancements in stem cell research have made it possible to differentiate human embryonic stem cells and induce pluripotent stem cells into various cell types, including myeloid cells, offering a promising new approach to generate myeloid cells for cell therapy. In this review, we explore the latest techniques for the genetic engineering of myeloid cells, discussing both established and emerging methodologies. We examine the challenges faced in this field and the therapeutic potential of engineered myeloid cells. We also describe examples of engineered macrophages, neutrophils, and dendritic cells in various disease contexts. By providing a detailed overview of the current state and future directions, we aim to highlight progress and ongoing efforts toward harnessing the full therapeutic potential of genetically engineered myeloid cells.

Colorectal cancer (CRC) remains a significant cause of cancer-related mortality worldwide. Despite advancements in surgery, chemotherapy, and radiotherapy, the effectiveness of these conventional treatments is limited, particularly in advanced cases. Therefore, transition to novel treatment is urgently needed. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has shown promise in improving outcomes for CRC patients. Notably, patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors often benefit from ICIs, while the majority of CRC cases, which exhibit proficient mismatch repair (pMMR) or microsatellite-stable (MSS) status, generally show resistance to this approach. It is assumed that the MSI phenotype cause some changes in the tumor microenvironment (TME), thus triggering antitumor immunity and leading to response to immunotherapy. Understanding these differences in the TME relative to MSI status is essential for developing more effective therapeutic strategies. This review provides an overview of the TME components in CRC and explores current approaches aimed at enhancing ICI efficacy in MSS CRC.

Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication.

We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts.

We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden.

Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.

This study aims to elucidate the therapeutic efficacy and safety of a taxane-based chemotherapy in combination with immune checkpoint inhibitors regimen in patients diagnosed with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

We retrospectively collected clinical data from 154 patients who received at least two cycles of PD-1 inhibitors in combination with a taxane-based chemotherapy as first-line treatment in seven hospitals in Hunan Province, between December 2018 and December 2023. These patients were subjected to long-term follow-up.

The study included 154 eligible patients, with a median follow-up period of 21.5 months. The median PFS was 8.7 months, while the median OS was 16.7 months. The 12-month PFS rate was 43.6%, and the 12-month OS rate was 60.1%. At 24 months, the PFS rate was 34.4%, and the OS rate was 36.9%. With 26 complete responses (16.9%) and 52 partial responses (33.8%), the ORR was 50.6%. Stable disease was observed in 54 patients (35.1%), resulting in a disease control rate of 85.7%, while 22 patients showed progressive disease. In the univariate analysis, the distant organ metastasis had a statistically significant impact on both PFS and OS. Subsequent radiotherapy following this protocol also showed a statistically significant effect on PFS and OS. However, radiotherapy before recurrent metastasis did not significantly affect PFS, though it did have a significant impact on OS. Other factors analyzed did not show a statistically significant effect on PFS and OS. Multivariate analysis indicated that the distant organ metastasis and subsequent radiotherapy following this protocol were independent prognostic factors for PFS in patients with R/M HNSCC, and the latter was also an independent prognostic factor for OS in these patients. Regarding safety, during treatment anemia was observed in 97 patients, leukopenia in 64, neutropenia in 33, thrombocytopenia in 28, transaminase elevation in 46, hypothyroidism in 46 patients, and one patient stopped taking the medication due to a serious adverse reaction. No treatment-related deaths occurred.

The combination of PD-1 inhibitors with a a taxane-based chemotherapy regimen as a first-line treatment for R/M HNSCC patients demonstrates good therapeutic efficacy and acceptable safety profiles.

As immune-checkpoint inhibitors (ICIs) therapy has made great strides in hepatocellular carcinoma (HCC) treatment, improving patient response to this strategy has become the main focus of research. Accumulating evidence has shown that m6A methylation plays a crucial role in the tumorigenesis and progression of HCC, while the precise impact of the m6A demethylase ALKBH5 on the tumor immune microenvironment (TIME) of HCC remains poorly defined. The clinical significance of ALKBH5 and TIM3 were evaluated in human HCC tissues. The biological function of ALKBH5 was analyzed in vitro and in vivo. The HCC molecular subtypes were identified based on key ALKBH5-regulated methylation-related genes (MRGs). The differences in survival, clinical features, TIME and immunotherapy response between these two subtypes were then evaluated. The regulation of ALKBH5 on TIM3 was detected by qPCR, western blotting and MeRIP. ALKBH5 was downregulated in HCC and associated with worse prognosis. ALKBH5 inhibited the proliferation and migration activities of HCC cells in vitro and in vivo. The HCC subtype with high expression of key MRGs was characterized by immunosuppression phenotypes and a worse response to ICIs. Moreover, TIM3 was identified as a target of ALKBH5. Upregulated TIM3 level was negatively correlated with survival in HCC. The results of this study suggest that ALKBH5 is an important regulator in HCC progression. ALKBH5 exerts its influence on the TIME and immunotherapy response by targeting TIM3 in HCC. This work provides new insight into the correlation between m6A modification and ICI response, which may help provide therapeutic benefits to HCC patients.

Current cancer immunotherapies exhibit low response rates attributed to suppressive tumor immune microenvironments (TIMEs). To address these unfavorable TIMEs, supplementation with tumor-associated antigens and stimulation of immune cells at target sites are indispensable for eliciting anti-tumoral immune responses. Previous research has explored the induction of immunotherapy through multiple injections and implants; however, these approaches lack consideration for patient convenience and the implementation of finely tunable immune response control systems to mitigate the side effects of over-inflammatory responses, such as cytokine storms. In this context, we describe a patient-centric nano-gel-nano system capable of sustained generation of tumor-associated antigens and release of adjuvants. This is achieved through the specific delivery of drugs to cancer cells and antigens/adjuvants to immune cells over the long term, maintaining proper concentrations within the tumor site with a single injection. This system demonstrates local immunity against tumors with a single injection, enhances the therapeutic efficacy of immune checkpoint blockades, and induces systemic and memory T cell responses, thus minimizing systemic side effects.

Triple-negative breast cancer (TNBC) is prone to relapse due to the lack of effective therapeutic targets. Macrophages are the most abundant immune cells in the tumor microenvironment (TME) of breast cancer. Targeting the cross-talk between macrophages and cancer cells provides a more efficient strategy for anti-tumor therapy. Toll-like receptors (TLRs) are important players involved in macrophage activation, and TLR agonists are known to play roles in cancer therapy. However, the combination strategy of TLR agonists with chemotherapy drugs is still not well characterized.

RT-PCR and Western blot were used to detect the expression of TLRs. The communication between breast cancer cells and macrophages were determined by co-culture in vitro. Tumor cells proliferation and migration were investigated by MTT assay and scratch wound assay. The effects of drug combinations and toxic side effects were assessed by immunohistochemistry and Hematoxylin & Eosin staining.

Expression of TLR3 and TLR4 were lower in breast tumor tissues compared with adjacent normal tissues. Patients with higher TLR3 or TLR4 expression levels had a better prognosis than those with lower expression levels. TLR3/4 expression was significantly inhibited when breast cancer cells MDA-MB-231 and E0771 were conditioned-cultured with macrophages in vitro and was also inhibited by pirarubicin (THP). However, the combination of TLR agonists and THP could reverse this response and inhibit the proliferation and migration of breast cancer cells. Additionally, this combination significantly reduced the tumor volume and weight in the murine model, increased the expression of TLR3/4 in mouse breast tumors.

Our results provide new ideas for the combination strategy of THP with TLR agonists which improves prognosis of breast cancer.

Glycyrrhizin (GL) has immunoregulatory effects on various inflammatory diseases including hepatitis and nephritis. However, the mechanisms underlying the anti-inflammatory effect of GL on renal inflammation are not fully understood. Hepatorenal syndrome (HRS) is a functional acute renal impairment that occurs in severe liver disease, and we found that kidney injury also occurs in Con A-induced experimental hepatitis in mice. We previously found that GL can alleviate Con A-induced hepatitis by regulating the expression of IL-25 in the liver. We wanted to investigate whether GL can alleviate Con A-induced nephritis by regulating IL-25. IL-25 regulates inflammation by modulating type 2 immune responses, but the mechanism by which IL-25 affects kidney disease remains unclear. In this study, we found that the administration of GL enhanced the expression of IL-25 in renal tissues; the latter promoted the generation of type 2 macrophages (M2), which inhibited inflammation in the kidney caused by Con A challenge. IL-25 promoted the secretion of the inhibitory cytokine IL-10 by macrophages but inhibited the expression of the inflammatory cytokine IL-1β by macrophages. Moreover, IL-25 downregulated the Con A-mediated expression of Toll-like receptor (TLR) 4 on macrophages. By comparing the roles of TLR2 and TLR4, we found that TLR4 is required for the immunoregulatory effect of IL-25 on macrophages. Our data revealed that GL has anti-inflammatory effects on Con A-induced kidney injury and that the GL/IL-25/M2 axis participates in the anti-inflammatory process. This study suggested that GL is a potential therapeutic for protecting against acute kidney injury.

Paclitaxel, a potent chemotherapeutic agent derived from the bark of the Pacific yew tree, has demonstrated significant efficacy in the treatment of various cancers, including colon cancer. This comprehensive review delves into the conventional treatments for colon cancer, emphasizing the crucial role of paclitaxel in contemporary management strategies. It explores the intricate process of sourcing and synthesizing paclitaxel, highlighting the importance of its structural properties in its anticancer activity. The review further elucidates the mechanism of action of paclitaxel, its pharmacological effects, and its integration into chemotherapy regimens for colon cancer. Additionally, novel drug delivery systems, such as nanocarriers, liposomes, nanoparticles, microspheres, micelles, microemulsions, and niosomes, are examined for their potential to enhance the therapeutic efficacy of paclitaxel. The discussion extends to recent clinical trials and patents, showcasing advancements in paclitaxel formulations aimed at improving treatment outcomes. The review concludes with prospects in the field underscoring the ongoing innovation and potential breakthroughs in colon cancer therapy.

Ovarian cancer (OC) is the most common and deadly malignant tumor of the female reproductive system. When OC cells detach from the primary tumor and enter the ascitic microenvironment, they are present as individual cells or multicellular spheroids in ascites. These spheroids, composed of cancer and non‑malignant cells, are metastatic units and play a crucial role in the progression of OC. However, little is known about the mechanism of spheroid formation and dissemination. Tumor‑associated macrophages (TAMs) in the center of spheroids are key in spheroid formation and metastasis and provide a potential target for OC therapy. The present review summarizes the key biological features of spheroids, focusing on the role of TAMs in spheroid formation, survival and peritoneal metastasis, and the strategies targeting TAMs to provide new insights in treating OC.

Single-cell RNA sequencing (scRNAseq) of tumour-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies reveals potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identifies NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs that is confirmed at the protein level. STAB1 inhibition in vitro induces anti-tumour macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarises Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulates the patients' data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increases survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days + ) are resistant to tumour rechallenge. Anti-stabilin1 antibody enriches the tumours with CXCL9+ macrophages and Foxp3-ASO increases TBET cell infiltration. Our results suggest that targeting these molecules in immune cells may improve chemotherapy response in patients.

Tumor-associated macrophages (TAMs) are a phenotypically diverse, highly plastic population of cells in the tumor microenvironment (TME) that have long been known to promote cancer progression. In this review, we summarize TAM ontogeny and polarization, and then explore how TAMs enhance tumor cell migration through the TME, thus facilitating metastasis. We also discuss how chemotherapy and host factors including diet, obesity, and race, impact TAM phenotype and cancer progression. In brief, TAMs induce epithelial-mesenchymal transition (EMT) in tumor cells, giving them a migratory phenotype. They promote extracellular matrix (ECM) remodeling, allowing tumor cells to migrate more easily. TAMs also provide chemotactic signals that promote tumor cell directional migration towards blood vessels, and then participate in the signaling cascade at the blood vessel that allows tumor cells to intravasate and disseminate throughout the body. Furthermore, while chemotherapy can repolarize TAMs to induce an anti-tumor response, these cytotoxic drugs can also lead to macrophage-mediated tumor relapse and metastasis. Patient response to chemotherapy may be dependent on patient-specific factors such as diet, obesity, and race, as these factors have been shown to alter macrophage phenotype and affect cancer-related outcomes. More research on how chemotherapy and patient-specific factors impact TAMs and cancer progression is needed to refine treatment strategies for cancer patients.

A growing body of research has established a correlation between tumors and persistent chronic inflammatory infiltration. As a primary instigator of inflammation, the majority of microbiomes naturally residing within our bodies engage in a mutually beneficial symbiotic relationship. Nevertheless, alterations in the microbiome's composition or breaches in the normal barrier function can disrupt the internal environment's homeostasis, potentially leading to the development and progression of various diseases, including tumors. The investigation of tumor-related microbiomes has contributed to a deeper understanding of their role in tumorigenesis. This review offers a comprehensive overview of the microbiome alterations and the associated inflammatory changes in ovarian cancer. It may aid in advancing research to elucidate the mechanisms underlying the ovarian cancer-associated microbiome, providing potential theoretical support for the future development of microbiome-targeted antitumor therapies and early screening through convenient methods.

Chronic inflammation and NLRP3 inflammasome activation are among the determining factors of breast malignancies. Paclitaxel (PTX) is a drug used in breast cancer treatment which sustains prolonged inflammation, reducing the effectiveness of chemotherapy. Considering the impact of inflammatory processes in cancer progression, there is a strong concern to develop therapeutic strategy targeting NLRP3 inflammasome for triple-negative breast cancer (TNBC) treatment. Therefore, the aim of this study was to evaluate the potential of PTX and NLRP3 inflammasome modulation to counterbalance TNBC by inducing programmed cell death and inhibiting the activity of pro-inflammatory cytokines. The obtained results suggested the strong interaction between NLRP3 inflammasome and TNBC and revealed that pharmacological inhibition, using NLRP3-specific inhibitor MCC950, and genetic silencing of NLRP3 inflammasome using specific small interfering RNA, reduced inflammatory responses and facilitated PTX-determined tumor cell death. Thus, NLRP3 inflammasome manipulation in combination with anti-tumor drugs opens up new therapeutic perspectives for TNBC therapy.

Breast cancer is a significant global health issue. Tumor-associated macrophages (TAMs) are crucial in influencing the tumor microenvironment and the progression of the disease. TAMs exhibit remarkable plasticity in adopting distinct phenotypes ranging from pro-inflammatory and anti-tumorigenic (M1-like) to immunosuppressive and tumor-promoting (M2-like). This review elucidates the multifaceted roles of TAMs in driving breast tumor growth, angiogenesis, invasion, and metastatic dissemination. Significantly, it highlights the intricate crosstalk between TAMs and non-coding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, as a crucial regulatory mechanism modulating TAM polarization and functional dynamics that present potential therapeutic targets. Nanotechnology-based strategies are explored as a promising approach to reprogramming TAMs toward an anti-tumor phenotype. Various nanoparticle delivery systems have shown potential for modulating TAM polarization and inhibiting tumor-promoting effects. Notably, nanoparticles can deliver ncRNA therapeutics to TAMs, offering unique opportunities to modulate their polarization and activity.

Colorectal cancer (CRC) is a frequent gastrointestinal malignancy with high rates of morbidity and mortality; 85% of these tumours are proficient mismatch repair (pMMR)-microsatellite instability-low (MSI-L)/microsatellite stable (MSS) CRC known as 'cold' tumours that are resistant to immunosuppressive drugs. Monotherapy with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors is ineffective for treating MSS CRC, making immunotherapy for MSS CRC a bottleneck. Recent studies have found that the multi-pathway regimens combined with PD-1/PD-L1 inhibitors can enhance the efficacy of anti-PD-1/PD-L1 in MSS CRC by increasing the number of CD8+ T cells, upregulating PD-L1 expression and improving the tumour microenvironment. This paper reviews the research progress of PD-1/PD-L1 inhibitors in combination with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, oncolytic virus, intestinal flora, antiangiogenic agents, chemotherapy, radiotherapy and epigenetic drugs for the treatment of pMMR-MSI-L/MSS CRC.

Next-generation cancer treatments are expected not only to target cancer cells but also to simultaneously train immune cells to combat cancer while modulating the immune-suppressive environment of tumors and hosts to ensure a robust and lasting response. Achieving this requires carriers that can codeliver multiple therapeutics to the right cancer and/or immune cells while ensuring patient safety. Nanotechnology holds great potential for addressing these challenges. This article highlights the recent advances in nanoimmunotherapeutic development, with a focus on breast cancer. While immune checkpoint inhibitors (ICIs) have achieved remarkable success and lead to cures in some cancers, their response rate in breast cancer is low. The poor response rate in solid tumors is often associated with the low infiltration of anti-cancer T cells and an immunosuppressive tumor microenvironment (TME). To enhance anti-cancer T-cell responses, nanoparticles are employed to deliver ICIs, bispecific antibodies, cytokines, and agents that induce immunogenic cancer cell death (ICD). Additionally, nanoparticles are used to manipulate various components of the TME, such as immunosuppressive myeloid cells, macrophages, dendritic cells, and fibroblasts to improve T-cell activities. Finally, this article discusses the outlook, challenges, and future directions of nanoimmunotherapeutics.

Prostate cancer is primarily hormone-dependent, and medical treatments have focused on inhibiting androgen biosynthesis or signaling through various approaches. Despite significant advances with the introduction of androgen receptor signalling inhibitors (ARSIs), patients continue to progress to castration-resistant prostate cancer (CRPC), highlighting the need for targeted therapies that extend beyond hormonal blockade. Chimeric Antigen Receptor (CAR) T cells and other engineered immune cells represent a new generation of adoptive cellular therapies. While these therapies have significantly enhanced outcomes for patients with hematological malignancies, ongoing research is exploring the broader use of CAR T therapy in solid tumors, including advanced prostate cancer. In general, CAR T cell therapies are less effective against solid cancers with the immunosuppressive tumor microenvironment hindering T cell infiltration, activation and cytotoxicity following antigen recognition. In addition, inherent tumor heterogeneity exists in patients with advanced prostate cancer that may prevent durable therapeutic responses using single-target agents. These barriers must be overcome to inform clinical trial design and improve treatment efficacy. In this review, we discuss the innovative and rationally designed strategies under investigation to improve the clinical translation of cellular immunotherapy in prostate cancer and maximise therapeutic outcomes for these patients.

Background and Purpose: The continuous accumulation of M2 macrophages may potentially contribute to the development of kidney fibrosis in chronic kidney disease (CKD). The purpose of this study was to analyze the infiltration of M2 macrophages in uremic patients and to seek new strategies to slow down the progression of renal fibrosis. Methods: We conducted a comprehensive search for expression data pertaining to uremic samples within the Gene Expression Omnibus (GEO) database, encompassing the time frame from 2010 to 2022. Control and uremic differentially expressed genes (DEGs) were identified. Immune cell infiltration was investigated by CIBERSORT and modules associated with M2 macrophage infiltration were identified by weighted gene coexpression network analysis (WGCNA). Consistent genes were identified using the least absolute shrinkage and selection operator (LASSO) and selection and visualization of the most relevant features (SVM-RFE) methods to search for overlapping genes. Receiver operating characteristic (ROC) curves were examined for the diagnostic value of candidate genes. Quantitative real-time PCR (qPCR) examined the expression levels of candidate genes obtained from uremic patients in M2 macrophage. Results: A total of 1298 DEGs were identified within the GSE37171 dataset. Significant enrichment of DEGs was observed in 20 biological processes (BP), 19 cellular components (CC), 6 molecular functions (MF), and 70 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. CIBERSORT analysis observed a significant increase in B-cell memory, dendritic cell activation, M0, M1, M2, and plasma cell numbers in uremic samples. We identified the 10 most interrelated genes. In particular, adenomatous polyposis coli (APC) and zinc finger and BTB structural domain 2 (ZBTB2) were adversely associated with the infiltration of M2 macrophages. Importantly, the expression levels of APC and ZBTB2 were far lower in M2 macrophages from uremic patients than those in healthy individuals. Conclusion: The development of renal fibrosis may be the result of M2 macrophage infiltration promoted by APC and ZBTB2.

Small cell lung cancer (SCLC) is a highly malignant and poor-prognosis cancer, with most cases diagnosed at the extensive stage (ES). Amidst a landscape marked by limited progress in treatment modalities for ES-SCLC over the past few decades, the integration of immune checkpoint inhibitors (ICIs) with platinum-based chemotherapy has provided a milestone approach for improving prognosis, emerging as the new standard for initial therapy in ES-SCLC. However, only a minority of SCLC patients can benefit from ICIs, which frequently come with varying degrees of immune-related adverse events (irAEs). Therefore, it is crucial to investigate predictive biomarkers to screen potential beneficiaries of ICIs, mitigate the risk of side effects, and improve treatment precision. This review summarized potential biomarkers for predicting ICI response in ES-SCLC, with a primary focus on markers sourced from tumor tissue or peripheral blood samples. The former mainly included PD-L1 expression, tumor mutational burden (TMB), along with cellular or molecular components related to the tumor microenvironment (TME) and antigen presentation machinery (APM), molecular subtypes of SCLC, and inflammatory gene expression profiles. Circulating biomarkers predominantly comprised circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), cytokines, plasma autoantibodies, inflammation-related parameters, and blood TMB. We synthesized and analyzed the research progress of these potential markers. Notably, investigations into PD-L1 expression and TMB have been the most extensive, exhibiting preliminary predictive efficacy in salvage immunotherapy; however, consistent conclusions have yet to be reached across studies. Additionally, novel predictive markers developed based on TME composition, APM, transcriptomic and genomic features provide promising tools for precision immunotherapy. Circulating biomarkers offer the advantages of convenience, non-invasiveness, and a comprehensive reflection of tumor molecular characteristics. They may serve as alternative options for predicting immunotherapy efficacy in SCLC. However, there is a scarcity of studies, and the significant heterogeneity in research findings warrants attention.

Tumour-associated macrophages (TAMs) sustain a tumour-supporting and immunosuppressive milieu and therefore aggravate cancer prognosis. To modify TAM behaviour and unlock their anti-tumoural potential, novel TAM-reprogramming immunotherapies are being developed at an accelerating rate. At the same time, scientific discoveries have highlighted more sophisticated TAM phenotypes with complex biological functions and contradictory prognostic associations. To understand the evolving clinical landscape, we reviewed current and past clinically evaluated TAM-reprogramming cancer therapeutics and summarised almost 200 TAM-reprogramming agents investigated in more than 700 clinical trials. Observable overall trends include a high frequency of overlapping strategies against the same therapeutic targets, development of more complex strategies to improve previously ineffective approaches and reliance on combinatory strategies for efficacy. However, strong anti-tumour efficacy is uncommon, which encourages re-directing efforts on identifying biomarkers for eligible patient populations and comparing similar treatments earlier. Future endeavours will benefit from considering the shortcomings of past treatment strategies and accommodating the emerging complexity of TAM biology.

Osteosarcoma (OS) is a primary malignant bone tumor that emanates from mesenchymal cells, commonly found in the epiphyseal end of long bones. The highly recurrent and metastatic nature of OS poses significant challenges to the efficacy of treatment and negatively affects patient prognosis. Currently, available clinical treatment strategies primarily focus on maximizing tumor resection and reducing localized symptoms rather than the complete eradication of malignant tumor cells to achieve ideal outcomes. The biomaterials-boosted immunotherapy for OS is characterized by high effectiveness and a favorable safety profile. This therapeutic approach manipulates the tumor microenvironments at the cellular and molecular levels to impede tumor progression. This review delves into the mechanisms underlying the treatment of OS, emphasizing biomaterials-enhanced tumor immunity. Moreover, it summarizes the immune cell phenotype and tumor microenvironment regulation, along with the ability of immune checkpoint blockade to activate the autoimmune system. Gaining a profound comprehension of biomaterials-boosted OS immunotherapy is imperative to explore more efficacious immunotherapy protocols and treatment options in this setting.

Tumor-associated macrophages (TAMs) are inflammatory cells that are important components of the tumor microenvironment. TAMs are functionally heterogeneous and divided into two main subpopulations with distinct and opposite functions: M1 and M2 macrophages. The secretory function of TAMs is essential for combating infections, regulating immune responses, and promoting tissue repair. Extracellular vesicles (EVs) are nanovesicles that are secreted by cells. They play a crucial role in mediating intercellular information transfer between cells. EVs can be secreted by almost all types of cells, and they contain proteins, microRNAs, mRNAs, and even long non-coding RNAs (lncRNAs) that have been retained from the parental cell through the process of biogenesis. EVs can influence the function and behavior of target cells by delivering their contents, thus reflecting, to some extent, the characteristics of their parental cells. Here, we provide an overview of the role of M1 macrophages and their EVs in cancer therapy by exploring the impact of M1 macrophage-derived EVs (M1-EVs) on tumors by transferring small microRNAs. Additionally, we discuss the potential of M1-EVs as drug carriers and the possibility of reprogramming M2 macrophages into M1 macrophages for disease treatment. We propose that M1-EVs play a crucial role in cancer therapy by transferring microRNAs and loading them with drugs. Reprogramming M2 macrophages into M1 macrophages holds great promise in the treatment of cancers.

Ovarian cancer (OC) is a common gynecological malignancy with poor prognosis and substantial tumor heterogeneity. Due to the complex tumor immune microenvironment (TIME) among ovarian cancer, only a few patients have an immune response to immunotherapy. To investigate the differences in immune function and identify potential biomarkers in OC, we established a prognostic risk scoring model (PRSM) with differential expression of immune-related genes (IRGs) to identify critical prognostic IRG signatures.

Single-sample gene set enrichment analysis (ssGSEA) was used to investigate the infiltration of various immune cells in 372 OC patients. Then, COX regression analysis and Lasso regression analysis were used to screen IRGs and construct PRSM. Next, the immunotherapy sensitivity of different risk groups regarding the immune checkpoint expression and tumor mutation burden was evaluated. Finally, a nomogram was created to guide the clinical evaluation of the patient prognosis.

In this study, 320 immune-related genes (IRGs) were identified, 13 of which were selectively incorporated into a Prognostic Risk Scoring Model (PRSM). This model revealed that the patients in the high-risk group were characterized as having poorer prognosis, lower expression of immune checkpoints, and decreased tumor mutation load levels compared with those in the low-risk group. The nomogram based on the risk score can distinguish the risk subtypes and individual prognosis of patients with OC. Additionally, M1 macrophages may be the critical target for immunotherapy in OC patients.

With the in-depth analysis of the immune microenvironment of OC, the PRSM was constructed to predict the OC patient prognosis and identify the subgroup of the patients benefiting from immunotherapy.

Korean mistletoe (Viscum album L. var. coloratum) is renowned for its medicinal properties, including anti-cancer and immunoadjuvant effects. This study aimed to elucidate the mechanisms by which Korean mistletoe lectin (V. album L. var. coloratum agglutinin; VCA) modulates breast cancer cell apoptosis and macrophage polarization. The specific objectives were to (1) investigate the direct effects of VCA on MCF-7 breast cancer cells and THP-1-derived M1/M2 macrophages; (2) analyze the impact of VCA on the paracrine interactions between these cell types; and (3) compare the efficacy of VCA in 2D vs. 3D co-culture models to bridge the gap between in vitro and in vivo studies. We employed both 2D and 3D models, co-culturing human M1/M2 macrophages with human MCF-7 breast cancer cells in a Transwell system. Our research demonstrated that M1 and M2 macrophages significantly influenced the immune and apoptotic responses of breast cancer cells when exposed to VCA. M1 macrophages exhibited cytotoxic characteristics and enhanced VCA-induced apoptosis in both 2D and 3D co-culture models. Conversely, M2 macrophages initially displayed a protective effect by reducing apoptosis in breast cancer cells, but this protective effect was reversed upon exposure to VCA. Furthermore, our findings illustrate VCA's ability to modulate M1 and M2 polarization in breast cancer cells. Finally, the use of magnetic 3D cell cultures suggests their potential to yield results comparable to conventional 2D cultures, bridging the gap between in vitro and in vivo studies.

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, it is also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.