Dual effects of radiotherapy on tumor microenvironment and its contribution towards the development of resistance to immunotherapy in gastrointestinal and thoracic cancers

Hu B., guo L., hua L., Wang J.

Introduction: This study aimed to outline the pre-clinical efficacy and safety pharmacology of PEGylated recombinant human endostatin (M2ES) according to the requirements of new drug application. background: These studies aimed to outline the pre-clinical efficacy and safety pharmacology of PEGylated recombinant human endostatin (M2ES) according to the requirements of new drug application. Method: The purity of M2ES was evaluated by using silver staining. Transwell migration assay was applied to detect the bioactivity of M2ES in vitro. The antitumor efficacy of M2ES was evaluated in an athymic nude mouse xenograft model of pancreatic cancer (Panc-1) and gastric cancer (MNK45). BALB/C mice were treated with different doses of M2ES (6, 12 and 24 mg/kg) intravenously, both autonomic activity and cooperative sleep were monitored before and after drug administration. The apparent molecular weight of M2ES was about 50 kDa, and the purity was greater than 98%. objective: To investigate the pre-clinical efficacy and safety pharmacology of M2ES. Result: Compared with the control group, M2ES significantly inhibits human microvascular endothelial cells (HMECs) cell migration in vitro. Notably, weekly administration of M2ES showed a significant antitumor efficacy when compared with the control group. Treatment of M2ES (24mg/kg or below) showed no obvious effect on both autonomic activity and hypnosis. method: The purity of M2ES was evaluated by using silver staining. Transwell migration assay was applied to detect the bioactivity of M2ES in vitro. The antitumor efficacy of M2ES was evaluated in an athymic nude mouse xenograft model of pancreatic cancer (Panc-1) and gastric cancer (MNK45). BALB/C mice were treated with different doses of M2ES (6, 12 and 24 mg/kg) intravenously, both autonomic activity and cooperative sleep were monitored before and after drug administration. Conclusion: On the basis of the pre-clinical efficacy and safety pharmacology data of M2ES, M2ES can be authorized to carry out further clinical studies. result: The apparent molecular weight of M2ES was about 50 kDa, and the purity was greater than 98%. Compared with control group, M2ES significantly inhibits human microvascular endothelial cells (HMECs) cell migration in vitro. Notably, weekly administration of M2ES showed a significant antitumor efficacy when compared with the control group. Treatment of M2ES (24mg/kg or below) showed no obvious effect on the autonomic activity of mice, and had no significant synergistic hypnotic effect with the subthreshold hypnotic dose of pentobarbital sodium. other: no

Akhtar S., Shah A.A., Ahmad S., Yadav M.K., Raza K., Kamal M.A.

Background: Epidermal growth factor receptor (EGFR/HER-1) and its role in tumor development and progression through the mechanism of tumor angiogenesis is prevalent in non-small lung cancer, head and neck cancer, cholangiocarcinoma & glioblastoma. Previous treatments targeting the oncogenic activity of EGFR's kinase domain have been hindered by acquired mutational resistance and side effects from existing drugs like erlotinib, highlighting the need for new EGFR inhibitors through structure- based drug designing. Objective: The research aims to develop novel quinazoline derivatives through structure-based virtual screening, molecular docking, and molecular dynamics simulation to potentially interact with EGFR's kinase domain and impede tumor angiogenic phenomenon. Methods: Quinazoline derivatives were retrieved and filtered from the PubChem database using structure- based virtual screening and the Lipinski rule of five drug-likeness studies. Molecular docking-based virtual screening methods and molecular dynamics simulation were then carried out to identify top leads. Results: A total of 1000 quinazoline derivatives were retrieved, with 671 compounds possessing druglike properties after applying Lipinski filters. Further filtration using ADME and toxicity filters yielded 28 compounds with good pharmacokinetic profiles. Docking-based virtual screening identified seven compounds with better binding scores than the control drug, dacomitinib. After cross-checking binding scores, three top compounds QU524, QU571, and QU297 were selected for molecular dynamics simulation study of 100 ns interval using Desmond module of Schrodinger maestro to understand their conformational stability. Conclusion: The research results showed that the selected quinazoline leads exhibited better binding affinity and conformational stability than the control drug, erlotinib. These compounds also had good pharmacokinetic and pharmacodynamic profiles and did not violate Lipinski’s rule of five limits. The findings suggest that these leads have the potential to target EGFR's kinase domain and inhibit the EGFR-associated phenomenon of tumor angiogenesis.

Park S.J., Min H.J., Yoon C., Kim S.H., Kim J.H., Lee S.Y.

Perineural invasion and radioresistance are the main determinants of treatment outcomes in oral squamous cell carcinoma (OSCC), but the exact mechanism is still unknown. We conducted an in vitro experiment to evaluate the role of integrin β1 (ITGB1) in the perineural invasion, radioresistance, and tumor aggressiveness of OSCC. Two OSCC cell lines (SCC25, SCC15) and radiation-induced radioresistant OSCC cell lines were used in this study. The expression of ITGB1 was compared between control radiosensitive and radioresistant OSCC cell lines. ITGB1 was inhibited by small hairpin RNA, and then the adhesion to neuronal cells, responsiveness to radiation, and aggressiveness of both OSCC cell lines were evaluated. Expression of ITGB1 and adhesion to neuronal cells were increased in radioresistant OSCC compared with control radiosensitive OSCC, and increased ITGB1 expression was more prominent in cancer stem cell-like cells. When the expression of ITGB1 was inhibited, the adhesion to neuronal cells, resistance to radiation, and invasion and migration of radioresistant OSCC were significantly reduced. Moreover, the expression of cancer stem cell markers and size of spheroid formations were also significantly attenuated by inhibiting ITGB1. These findings suggest that ITGB1 may be a significant contributor to perineural invasion and the maintenance of radioresistance in OSCC cells, and is associated with cancer stem cell-like cells. Furthermore, our results suggest a possible relationship between perineural invasion and radioresistance of OSCC. More detailed research is warranted to evaluate the role of ITGB1 as a novel emerging therapeutic target for radioresistant OSCC.

Guo S., Yuan J., Meng X., Feng X., Ma D., Han Y., Li K.

The tumour microenvironment (TME) is critical for the initiation, progression, and metastasis of tumours, and cancer-associated fibroblasts (CAFs) are the most dominant cells and have attracted interest as targets for cancer therapy among the stromal components within the TME. Currently, most of the identified CAF subpopulations are believed to exhibit suppressive effects on antitumour immunity. However, accumulating evidence indicates the presence of immunostimulatory CAF subpopulations, which play an important role in the maintenance and amplification of antitumour immunity, in the TME. Undoubtedly, these findings provide novel insights into CAF heterogeneity. Herein, we focus on summarizing CAF subpopulations that promote antitumour immunity, the surface markers of these populations, and possible immunostimulatory mechanisms in the context of recent advances in research on CAF subpopulations. In addition, we discuss the possibility of new therapies targeting CAF subpopulations and conclude with a brief description of some prospective avenues for CAF research.

Zhang Y., Peng Q., Zheng J., Yang Y., Zhang X., Ma A., Qin Y., Qin Z., Zheng X.

Lactate is an end product of glycolysis. Owing to the lactate shuttle concept introduced in the early 1980s, increasing researchers indicate lactate as a critical energy source for mitochondrial respiration and as a precursor of gluconeogenesis. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells, resulting in diverse biological consequences including decreased lipolysis, immune regulation, and anti-inflammation wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, increasing evidence reveals that lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, which accounts for its key role in immune modulation and maintenance of homeostasis. Here, we summarize the function and mechanism of lactate and lactylation in tumor metabolism and microenvironment.

Viswanath D., Park J., Misra R., Pizzuti V.J., Shin S., Doh J., Won Y.

AbstractRare but consistent reports of abscopal remission in patients challenge the notion that radiotherapy (RT) is a local treatment; radiation‐induced cancer cell death can trigger activation and recruitment of dendritic cells to the primary tumor site, which subsequently initiates systemic immune responses against metastatic lesions. Although this abscopal effect was initially considered an anomaly, combining RT with immune checkpoint inhibitor therapies has been shown to greatly improve the incidence of abscopal responses via modulation of the immunosuppressive tumor microenvironment. Preclinical studies have demonstrated that nanomaterials can further improve the reliability and potency of the abscopal effect for various different types of cancer by (1) altering the cell death process to be more immunogenic, (2) facilitating the capture and transfer of tumor antigens from the site of cancer cell death to antigen‐presenting cells, and (3) co‐delivering immune checkpoint inhibitors along with radio‐enhancing agents. Several unanswered questions remain concerning the exact mechanisms of action for nanomaterial‐enhanced RT and for its combination with immune checkpoint inhibition and other immunostimulatory treatments in clinically relevant settings. The purpose of this article is to summarize key recent developments in this field and also highlight knowledge gaps that exist in this field. An improved mechanistic understanding will be critical for clinical translation of nanomaterials for advanced radio‐immunotherapy.This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Zhang Y., Lv N., Li M., Liu M., Wu C.

AbstractCancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment that are involved in multiple aspects of cancer progression and considered contributors to tumor immune escape. CAFs exhibit a unique radiation resistance phenotype, and can survive clinical radiation doses; however, ionizing radiation can induce changes in their secretions and influence tumor progression by acting on tumor and immune cells. In this review, we describe current knowledge of the effects of radiation therapies on CAFs, as well as summarizing understanding of crosstalk among CAFs, tumor cells, and immune cells. We highlight the important role of CAFs in radiotherapy resistance, and discuss current and future radiotherapy strategies for targeting CAFs.

Aggarwal D., Yang J., Salam M.A., Sengupta S., Al-Amin M.Y., Mustafa S., Khan M.A., Huang X., Pawar J.S.

Cancer is one of the deadliest diseases, causing million of deaths each year globally. Conventional anti-cancer therapies are non-targeted and have systemic toxicities limiting their versatile applications in many cancers. So, there is an unmet need for more specific therapeutic options that will be effective as well as free from toxicities. Antibody-drug conjugates (ADCs) are suitable alternatives with the right potential and improved therapeutic index for cancer therapy. The ADCs are highly precise new class of biopharmaceutical products that covalently linked a monoclonal antibody (mAb) (binds explicitly to a tumor-associated surface antigen) with a customized cytotoxic drug (kills cancer cells) and tied via a chemical linker (releases the drug). Due to its precise design, it brings about the target cell killing sparing the normal counterpart and free from the toxicities of conventional chemotherapy. It has never been so easy to develop potential ADCs for successful therapeutic usage. With relentless efforts, it took almost a century for scientists to advance the formula and design ADCs for its current clinical applications. Until now, several ADCs have passed successfully through preclinical and clinical trials and because of proven efficacy, a few are approved by the FDA to treat various cancer types. Even though ADCs posed some shortcomings like adverse effects and resistance at various stages of development, with continuous efforts most of these limitations are addressed and overcome to improve their efficacy. In this review, the basics of ADCs, physical and chemical properties, the evolution of design, limitations, and future potentials are discussed.

Pontoriero A., Critelli P., Chillari F., Ferrantelli G., Sciacca M., Brogna A., Parisi S., Pergolizzi S.

Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients’ T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10–20 Gy/fractions) converts immunologically “cold” tumors into “hot” ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5–10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.

Greimelmaier K., Klopp N., Mairinger E., Wessolly M., Borchert S., Steinborn J., Schmid K.W., Wohlschlaeger J., Mairinger F.D.

Background: Colorectal cancer (CRC) is still one of the leading causes of cancer death worldwide, emphasizing the need for further diagnostic and therapeutic approaches. Cancer invasion and metastasis are affected by the tumor microenvironment (TME), with cancer-associated fibroblasts (CAF) being the predominant cellular component. An important marker for CAF is fibroblast activation protein-α (FAP) which has been evaluated as therapeutic target for, e.g., radioligand therapy. The aim of this study was to examine CRC regarding the FAP expression as a candidate for targeted therapy.Methods: 67 CRC, 24 adenomas, 18 tissue samples of inflammation sites and 28 non-neoplastic, non-inflammatory tissue samples of colonic mucosa were evaluated for immunohistochemical FAP expression of CAF in tissue microarrays. The results were correlated with clinicopathological data, tumor biology and concurrent expression of additional immunohistochemical parameters.Results: 53/67 (79%) CRC and 6/18 (33%) inflammatory tissue specimens showed expression of FAP. However, FAP was only present in 1/24 (4%) adenomas and absent in normal mucosa (0/28). Thus, FAP expression in CRC was significantly higher than in the other investigated groups. Within the CRC cohort, expression of FAP did not correlate with tumor stage, grading or the MSI status. However, it was observed that tumors exhibiting high immunohistochemical expression of Ki-67, CD3, p53, and β-Catenin showed a significantly higher incidence of FAP expression.Conclusion: In the crosstalk between tumor cells and TME, CAF play a key role in carcinogenesis and metastatic spread. Expression of FAP was detectable in the majority of CRC but nearly absent in precursor lesions and non-neoplastic, non-inflammatory tissue. This finding indicates that FAP has the potential to emerge as a target for new diagnostic and therapeutic concepts in CRC. Additionally, the association between FAP expression and other immunohistochemical parameters displays the interaction between different components of the TME and demands further investigation.

Li X., Mu P.

Abstract Prostate cancer is a common malignancy driven by the androgen receptor (AR) pathway, with androgen deprivation therapy (ADT) being a standard treatment. However, the development of castration-resistant prostate cancer (CRPC) poses a significant challenge. CRPC is characterized by significantly increased tumor heterogeneity and lineage plasticity. Current research has primarily emphasized intrinsic tumor mechanisms, paying less attention to the role of the tumor microenvironment in cancer recurrence and drug resistance. In their recent study published in Cancer Cell, Wang and colleagues employed single-cell RNA sequencing in genetically engineered mouse models (GEMMs) with prostate tumors at different stages. They revealed that SPP1+ myofibroblastic cancer-associated fibroblasts (myCAFs), induced by ADT, play an instrumental role in CRPC development. Their work also underscores the association between therapy-induced phenotypic alterations of cancer-associated fibroblasts (CAFs) and disease progression. This discovery highlights the potential for stromal compartment targeting as a means to mitigate CRPC development and overcome treatment resistance.

Morgan A., Griffin M., Kameni L., Wan D.C., Longaker M.T., Norton J.A.

Pancreatic cancer is one of the deadliest forms of cancer with one of the lowest 5-year survival rates of all cancer types. A defining characteristic of pancreatic cancer is the existence of dense desmoplastic stroma that, when exposed to stimuli such as cytokines, growth factors, and chemokines, generate a tumor-promoting environment. Cancer-associated fibroblasts (CAFs) are activated during the progression of pancreatic cancer and are a crucial component of the tumor microenvironment (TME). CAFs are primarily pro-tumorigenic in their activated state and function as promoters of cancer invasion, proliferation, metastasis, and immune modulation. Aided by many signaling pathways, cytokines, and chemokines in the tumor microenvironment, CAFs can originate from many cell types including resident fibroblasts, mesenchymal stem cells, pancreatic stellate cells, adipocytes, epithelial cells, endothelial cells, and other cell types. CAFs are a highly heterogeneous cell type expressing a variety of surface markers and performing a wide range of tumor promoting and inhibiting functions. Single-cell transcriptomic analyses have revealed a high degree of specialization among CAFs. Some examples of CAF subpopulations include myofibrotic CAFs (myCAFs), which exhibit a matrix-producing contractile phenotype; inflammatory CAFs (iCAF) that are classified by their immunomodulating, secretory phenotype; and antigen-presenting CAFs (apCAFs), which have antigen-presenting capabilities and express Major Histocompatibility Complex II (MHC II). Over the last several years, various attempts have been undertaken to describe the mechanisms of CAF–tumor cell interaction, as well as CAF–immune cell interaction, that contribute to tumor proliferation, invasion, and metastasis. Although our understanding of CAF biology in cancer has steadily increased, the extent of CAFs heterogeneity and their role in the pathobiology of pancreatic cancer remains elusive. In this regard, it becomes increasingly evident that further research on CAFs in pancreatic cancer is necessary.

Shannon A.H., Manne A., Diaz Pardo D.A., Pawlik T.M.

Hepatocellular Carcinoma (HCC) is one of the most common cancers and a leading cause of cancer related death worldwide. Until recently, systemic therapy for advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B or C, was limited and ineffective in terms of long-term survival. However, over the past decade, immune check point inhibitors (ICI) combinations have emerged as a potential therapeutic option for patients with nonresectable disease. ICI modulate the tumor microenvironment to prevent progression of the tumor. Radiotherapy is a crucial tool in treating unresectable HCC and may enhance the efficacy of ICI by manipulating the tumor microenvironment and decreasing tumor resistance to certain therapies. We herein review developments in the field of ICI combined with radiotherapy for the treatment of HCC, as well as look at challenges associated with these treatment modalities, and review future directions of combination therapy.

Li Y., Wang C., Huang T., Yu X., Tian B.

Breast cancer deaths are primarily caused by metastasis. There are several treatment options that can be used to treat breast cancer. There are, however, a limited number of treatments that can either prevent or inhibit the spread of breast tumor metastases. Thus, novel therapeutic strategies are needed. Studies have increasingly focused on the importance of the tumor microenvironment (TME) in metastasis of breast cancer. As the most abundant cells in the TME, cancer-associated fibroblasts (CAFs) play important roles in cancer pathogenesis. They can remodel the structure of the extracellular matrix (ECM) and engage in crosstalk with cancer cells or other stroma cells by secreting growth factors, cytokines, and chemokines, as well as components of the ECM, which assist the tumor cells to invade through the TME and cause distant metastasis. Clinically, CAFs not only foster the initiation, growth, angiogenesis, invasion, and metastasis of breast cancer but also serve as biomarkers for diagnosis, therapy, and prediction of prognosis. In this review, we summarize the biological characteristics and subtypes of CAFs and their functions in breast cancer metastasis, focusing on their important roles in the diagnosis, prognosis, and treatment of breast cancer. Recent studies suggest that CAFs are vital partners of breast cancer cells that assist metastasis and may represent ideal targets for prevention and treatment of breast cancer metastasis.

Yang D., Liu J., Qian H., Zhuang Q.

AbstractCancer-associated fibroblasts (CAFs), as a central component of the tumor microenvironment in primary and metastatic tumors, profoundly influence the behavior of cancer cells and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Furthermore, the innate versatility and plasticity of CAFs allow their education by cancer cells, resulting in dynamic alterations in stromal fibroblast populations in a context-dependent manner, which highlights the importance of precise assessment of CAF phenotypical and functional heterogeneity. In this review, we summarize the proposed origins and heterogeneity of CAFs as well as the molecular mechanisms regulating the diversity of CAF subpopulations. We also discuss current strategies to selectively target tumor-promoting CAFs, providing insights and perspectives for future research and clinical studies involving stromal targeting.

Jiang Q., Chen Z., Jiang J., Chen Q., Lan H., Zhu J., Mao W.

Zhang A., Fan L., Liu Q., Zuo X., Zhu J.

ABSTRACTRadiation therapy can be categorised by particle type into photon, proton and heavy ion therapies. Proton radiotherapy is highlighted due to its unique physical properties, such as the Bragg peak and minimal exit dose, which offer superior dose distribution. This makes proton radiotherapy especially advantageous for treating tumours near vital organs with complex structures, such as gliomas near the brain, nasopharyngeal carcinoma near the brainstem and mediastinal tumours near the heart. Proton irradiation can induce distant effects through immunogenicity within the target area. The reduced low‐dose zone outside the target provides better lymphatic system protection and immune benefits. Additionally, combining proton radiotherapy with immunotherapy may offer further biological advantages. These features make proton radiotherapy a promising option in cancer treatment. This article may aid in the understanding of proton radiotherapy and its immune effects and lead to new effective options for tumour treatment.

Zhong L., Peng W., Sun J., Luo Y., Sheng H., Wu Y., Zhou T., Zhou C., Cao C.

Strzelec B., Chmielewski P.P., Taboła R.

Background/Objectives: The management of esophageal cancer (EC) remains a significant clinical challenge, particularly in optimizing therapeutic strategies for different stages and subgroups. This study assessed the impact of preoperative radiochemotherapy (CRT) on clinical staging and identified subgroups for whom definitive CRT (dCRT) may provide a favorable alternative to surgery. Methods: Sixty-one patients with esophageal adenocarcinoma or squamous cell carcinoma were enrolled. Pre-treatment staging included computed tomography, gastroscopy with biopsy, and comprehensive laboratory evaluations. Patients received preoperative CRT following the CROSS or dCRT protocols based on tumor stage. Surgical approaches included staged esophagectomy or single-stage Ivor Lewis procedures. Four patients declined surgery and were treated with dCRT. Postoperative outcomes were evaluated using pTNM classification. Follow-up included imaging and endoscopic surveillance. Statistical analyses assessed changes in staging and factors influencing treatment outcomes. Results: CRT significantly reduced T stage across the entire cohort (p = 0.0002), with complete pathological response (pT0N0M0) observed in 54.5% of patients following induction CRT (p = 0.0001). Male patients demonstrated a significant reduction in T stage (p = 0.0008), while a similar trend in females was not significant (p = 0.068). Among patients declining surgery, dCRT demonstrated acceptable oncologic control over a mean follow-up of 4 ± 0.79 years. Conclusions: Preoperative CRT effectively downstages EC and achieves high rates of response, especially in male patients. Therefore, dCRT may be a viable alternative in selected patients, emphasizing the need for individualized treatment strategies to optimize outcomes. These findings underscore the importance of refining multimodal approaches in EC care.

Greene G., Zonfa I., Ravasz Regan E.

AbstractThe tumor microenvironment aids cancer progression by promoting several cancer hallmarks, independent of cancer-related mutations. Biophysical properties of this environment, such as the stiffness of the matrix cells adhere to and local cell density, impact proliferation, apoptosis, and the epithelial to mesenchymal transition (EMT). The latter is rate-limiting step for invasion and metastasis, enhanced in hypoxic tumor environments but hindered by soft matrices and/or high cell densities. As these influences are often studied in isolation, the crosstalk between hypoxia, biomechanical signals, and the classic EMT driver TGF-β is not well mapped, limiting our ability to predict and anticipate cancer cell behaviors in changing tumor environments. To address this, we built a Boolean regulatory network model that integrates hypoxic signaling with a mechanosensitive model of EMT, which includes the EMT-promoting crosstalk of mitogens and biomechanical signals, cell cycle control, and apoptosis. Our model reproduces the requirement of Hif-1α for proliferation, the anti-proliferative effects of strong Hif-1α stabilization during hypoxia, hypoxic protection from anoikis, and hypoxia-driven mechanosensitive EMT. We offer experimentally testable predictions about the effect of VHL loss on cancer hallmarks, with or without secondary oncogene activation. Taken together, our model serves as a predictive framework to synthesize the signaling responses associated with tumor progression and metastasis in healthy vs. mutant cells. Our single-cell model is a key step towards more extensive regulatory network models that cover damage-response and senescence, integrating most cell-autonomous cancer hallmarks into a single model that can, in turn, control the behavior of in silico cells within a tissue model of epithelial homeostasis and carcinoma.Author SummaryThe cellular environment in and around a tumor can aid cancer progression by promoting several cancer hallmarks. This environment can affect growth and cell death, as well as a phenotype change that renders cells migratory and invasive: the epithelial to mesenchymal transition. Hypoxia (low oxygen availability) is known to promote this transition, while the attachment of cells to soft matrices or high cell density environments hinders it. These influences are often studied in isolation. As a result, their crosstalk is poorly understood. To address this, we have built a network model of cellular regulation that integrates a cell’s responses to hypoxia, the biophysical environment, and growth signals to model cell division, death, and the epithelial to mesenchymal transition in environments cells encounter during metastatic tumor progression. Our model reproduces a wide range of experimental cell responses and offers experimentally testable predictions about the emergence of cancer hallmarks driven mutations that affect the hypoxic response. Our single-cell model is a key step towards more extensive cell-scale models that also include cell aging and damage response. These, in turn, can serve as building blocks of a larger tissue model of healthy vs. cancerous epithelia.

El-Tanani M., Rabbani S.A., Babiker R., Rangraze I., Kapre S., Palakurthi S.S., Alnuqaydan A.M., Aljabali A.A., Rizzo M., El-Tanani Y., Tambuwala M.M.

This comprehensive review delves into the pivotal role of the tumor microenvironment (TME) in cancer metastasis and therapeutic response, offering fresh insights into the intricate interplay between cancer cells and their surrounding milieu. The TME, a dynamic ecosystem comprising diverse cellular and acellular elements, not only fosters tumor progression but also profoundly affects the efficacy of conventional and emerging cancer therapies. Through nuanced exploration, this review illuminates the multifaceted nature of the TME, elucidating its capacity to engender drug resistance via mechanisms such as hypoxia, immune evasion, and the establishment of physical barriers to drug delivery. Moreover, it investigates innovative therapeutic approaches aimed at targeting the TME, including stromal reprogramming, immune microenvironment modulation, extracellular matrix (ECM)-targeting agents, and personalized medicine strategies, highlighting their potential to augment treatment outcomes. Furthermore, this review critically evaluates the challenges posed by the complexity and heterogeneity of the TME, which contribute to variable therapeutic responses and potentially unintended consequences. This underscores the need to identify robust biomarkers and advance predictive models to anticipate treatment outcomes, as well as advocate for combination therapies that address multiple facets of the TME. Finally, the review emphasizes the necessity of an interdisciplinary approach and the integration of cutting-edge technologies to unravel the intricacies of the TME, thereby facilitating the development of more effective, adaptable, and personalized cancer treatments. By providing critical insights into the current state of TME research and its implications for the future of oncology, this review highlights the dynamic and evolving landscape of this field.

Wu Y., Cao Y., Chen L., Lai X., Zhang S., Wang S.

AbstractExosomes are increasingly recognized as important mediators of intercellular communication in cancer biology. Exosomes can be derived from cancer cells as well as cellular components in tumor microenvironment. After secretion, the exosomes carrying a wide range of bioactive cargos can be ingested by local or distant recipient cells. The released cargos act through a variety of mechanisms to elicit multiple biological effects and impact most if not all hallmarks of cancer. Moreover, owing to their excellent biocompatibility and capability of being easily engineered or modified, exosomes are currently exploited as a promising platform for cancer targeted therapy. In this review, we first summarize the current knowledge of roles of exosomes in risk and etiology, initiation and progression of cancer, as well as their underlying molecular mechanisms. The aptamer-modified exosome as a promising platform for cancer targeted therapy is then briefly introduced. We also discuss the future directions for emerging roles of exosome in tumor biology and perspective of aptamer-modified exosomes in cancer therapy.

Song D., Ding Y.

Radiotherapy is one important treatment for malignant tumours. It is widely believed today that radiotherapy has not only been used as a local tumour treatment method, but also can induce systemic anti-tumour responses by influencing the tumour microenvironment, but its efficacy is limited by the tumour immunosuppression microenvironment. With the advancement of technology, immunotherapy has entered a golden age of rapid development, gradually occupying a place in clinical tumour treatment. Regulatory T cells (Tregs) widely distributing in the tumour microenvironment play an important role in mediating tumour development. This article analyzes immunotherapy, the interaction between Tregs, tumours and radiotherapy. It briefly introduces immunotherapies targeting Tregs, aiming to provide new strategies for radiotherapy combined with Immunotherapy.