As the most common and aggressive type of primary brain tumor in adults, glioblastoma is estimated to end over 10,000 lives each year in the United States alone. Stand treatment for glioblastoma, including surgery followed by radiotherapy and chemotherapy (i.e., Temozolomide), has been largely unchanged since early 2000. Cancer immunotherapy has significantly shifted the paradigm of cancer management in the past decade with various degrees of success in treating many hematopoietic cancers and some solid tumors, such as melanoma and non-small cell lung cancer (NSCLC). However, little progress has been made in the field of neuro-oncology, especially in the application of immunotherapy to glioblastoma treatment. In this review, we attempted to summarize the common drug resistance mechanisms in glioblastoma from Temozolomide to immunotherapy. Our intent is not to repeat the well-known difficulty in the area of neuro-oncology, such as the blood-brain barrier, but to provide some fresh insights into the molecular mechanisms responsible for resistance by summarizing some of the most recent literature. Through this review, we also hope to share some new ideas for improving the immunotherapy outcome of glioblastoma treatment.

Aim: Acquired resistance to the targeted agent cetuximab poses a significant challenge in finding effective anti-cancer treatments for head and neck squamous cell carcinoma (HNSCC). To accurately study novel combination treatments, suitable preclinical mouse models for cetuximab resistance are key yet currently limited. This study aimed to optimize an acquired cetuximab-resistant mouse model, with preservation of the innate immunity, ensuring intact antibody-dependent cellular cytotoxicity (ADCC) functionality.

Methods: Cetuximab-sensitive and acquired-resistant HNSCC cell lines, generated in vitro, were subcutaneously engrafted in Rag2 knock-out (KO), BALB/c Nude and CB17 Scid mice with/without Matrigel or Geltrex. Once tumor growth was established, mice were intraperitoneally injected twice a week with cetuximab for a maximum of 3 weeks. In addition, immunohistochemistry was used to evaluate the tumor and its microenvironment.

Results: Despite several adjustments in cell number, cell lines and the addition of Matrigel, Rag2 KO and BALB/C Nude mice proved to be unsuitable for xenografting our HNSCC cell lines. Durable tumor growth of resistant SC263-R cells could be induced in CB17 Scid mice. However, these cells had lost their resistance phenotype in vivo. Immunohistochemistry revealed a high infiltration of macrophages in cetuximab-treated SC263-R tumors. FaDu-S and FaDu-R cells successfully engrafted into CB17 Scid mice and maintained their sensitivity/resistance to cetuximab.

Conclusion: We have established in vivo HNSCC mouse models with intact ADCC functionality for cetuximab resistance and sensitivity using the FaDu-R and FaDu-S cell lines, respectively. These models serve as valuable tools for investigating cetuximab resistance mechanisms and exploring novel drug combination strategies.

The induction of cell death is recognized as a potent strategy for cancer treatment. Apoptosis is an extensively studied form of cell death, and multiple anticancer drugs exert their therapeutic effects by inducing it. Nonetheless, apoptosis evasion is a hallmark of cancer, rendering cancer cells resistant to chemotherapy drugs. Consequently, there is a growing interest in exploring novel non-apoptotic forms of cell death, such as ferroptosis, necroptosis, pyroptosis, and paraptosis. Natural compounds with anticancer properties have garnered significant attention due to their advantages, including a reduced risk of drug resistance. Over the past two decades, numerous natural compounds have been discovered to exert anticancer and anti-resistance effects by triggering these four non-apoptotic cell death mechanisms. This review primarily focuses on these four non-apoptotic cell death mechanisms and their recent advancements in overcoming drug resistance in cancer treatment. Meanwhile, it highlights the role of natural compounds in effectively addressing cancer drug resistance through the induction of these forms of non-apoptotic cell death.

Tumors survive by creating a tumor microenvironment (TME) that suppresses antitumor immunity. The TME suppresses the immune system by limiting antigen presentation, inhibiting lymphocyte and natural killer (NK) cell activation, and facilitating T cell exhaustion. Checkpoint inhibitors like anti-PD-1 and anti-CTLA4 are immunostimulatory antibodies, and their blockade extends the survival of some but not all cancer patients. Extracellular adenosine triphosphate (ATP) is abundant in inflamed tumors, and its metabolite, adenosine (ADO), is a driver of immunosuppression mediated by adenosine A2A receptors (A2AR) and adenosine A2B receptors (A2BR) found on tumor-associated lymphoid and myeloid cells. This review will focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity.

The use of immune checkpoint inhibitors (ICIs) has increased exponentially in the past decade, although its progress specifically for breast cancer has been modest. The first U.S. Food and Drug Administration approval for ICI in breast cancer came in 2019, eight years after the first-ever approval of an ICI. At present, current indications for ICIs are relevant only to a subset of patients with triple-negative breast cancer, or those displaying high microsatellite instability or deficiency in the mismatch repair protein pathway. With an increasing understanding of the limitations of using ICIs, which stem from breast cancer being innately poorly immunogenic, as well as the presence of various intrinsic and acquired resistance pathways, ongoing trials are evaluating different combination therapies to overcome these barriers. In this review, we aim to describe the development timeline of ICIs and resistance mechanisms limiting their utility, and summarise the available approaches and ongoing trials relevant to overcoming each resistance mechanism.

Drug resistance that affects patients universally is a major challenge in cancer therapy. The development of drug resistance in cancer cells is a multifactor event, and its process involves numerous mechanisms that allow these cells to evade the effect of treatments. As a result, the need to understand the molecular mechanisms underlying cancer drug sensitivity is imperative. Traditional 2D cell culture systems have been utilized to study drug resistance, but they often fail to mimic the 3D milieu and the architecture of real tissues and cell-cell interactions. As a result of this, 3D cell culture systems are now considered a comprehensive model to study drug resistance in vitro. Cancer cells exhibit an in vivo behavior when grown in a three-dimensional environment and react to therapy more physiologically. In this review, we discuss the relevance of main 3D culture systems in the study of potential approaches to overcome drug resistance and in the identification of personalized drug targets with the aim of developing patient-specific treatment strategies that can be put in place when resistance emerges.

Cancer drug resistance has become one of the main challenges for the failure of chemotherapy, greatly limiting the selection and use of anticancer drugs and dashing the hopes of cancer patients. The emergence of supramolecular host-guest nanosystems has brought the field of supramolecular chemistry into the nanoworld, providing a potential solution to this challenge. Compared with conventional chemotherapeutic platforms, supramolecular host-guest nanosystems can reverse cancer drug resistance by increasing drug uptake, reducing drug efflux, activating drugs, and inhibiting DNA repair. Herein, we summarize the research progress of supramolecular host-guest nanosystems for overcoming cancer drug resistance and discuss the future research direction in this field. It is hoped that this review will provide more positive references for overcoming cancer drug resistance and promoting the development of supramolecular host-guest nanosystems.

Chronic lymphocytic leukemia (CLL) is common amongst leukemic malignancies, prompting dedicated investigation throughout the years. Over the last decade, the treatment for CLL has significantly advanced with agents targeting B-cell lymphoma 2 (BCL2), Bruton’s tyrosine kinase, and CD20. Single agents or combinations of these targets have proven efficacy. Unfortunately, resistance to one or multiple of the new treatment targets develops. Our review investigates various mechanisms of resistance to BCL2 inhibitors, including mutations in BCL2, alterations in the Bcl protein pathway, epigenetic modifications, genetic heterogeneity, Richter transformation, and alterations in oxidative phosphorylation. Additionally, the review will discuss potential avenues to overcome this resistance with novel agents such as bispecific antibodies, Bruton’s tyrosine kinase (BTK) degraders, non-covalent BTK inhibitors, and chimeric antigen receptor T (CART).

Multiple myeloma (MM) is a type of hematological cancer that occurs when B cells become malignant. Various drugs such as proteasome inhibitors, immunomodulators, and compounds that cause DNA damage can be used in the treatment of MM. Autophagy, a type 2 cell death mechanism, plays a crucial role in determining the fate of B cells, either promoting their survival or inducing cell death. Therefore, autophagy can either facilitate the progression or hinder the treatment of MM disease. In this review, autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response (UPR), bone marrow microenvironment (BMME), drug resistance, hypoxia, DNA repair and transcriptional regulation, and apoptosis. The genes that are effective in each mechanism and research efforts on this subject were discussed in detail. Signaling pathways targeted by new drugs to benefit from autophagy in MM disease were covered. The efficacy of drugs that regulate autophagy in MM was examined, and clinical trials on this subject were included. Consequently, among the autophagy mechanisms that are effective in MM, the most suitable ones to be used in the treatment were expressed. The importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was emphasized. Ultimately, this review aims to provide a comprehensive overview of MM disease, encompassing autophagy mechanisms, drugs, clinical studies, and further studies.

Renal cell carcinoma (RCC), the most prevalent type of kidney cancer, is a significant cause of cancer morbidity and mortality worldwide. Antiangiogenic tyrosine kinase inhibitors (TKIs), in combination with immune checkpoint inhibitors (ICIs), are among the first-line treatment options for patients with advanced RCC. These therapies target the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase pathway and other kinases crucial to cancer proliferation, survival, and metastasis. TKIs have yielded substantial improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced RCC. However, nearly all patients eventually progress on these drugs as resistance develops. This review provides an overview of TKI resistance in RCC and explores different mechanisms of resistance, including upregulation of alternative proangiogenic pathways, epithelial-mesenchymal transition (EMT), decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration, alterations in the tumor microenvironment including bone marrow-derived cells (BMDCs) and tumor-associated fibroblasts (TAFs), and genetic factors such as single nucleotide polymorphisms (SNPs). A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKI resistance, thereby improving outcomes for patients with advanced RCC.