Over the last decade, based on the extensive development of preclinical animal studies and clinical trials, the efficacy, and mechanisms of immunotherapy have been fully explored. Significant and lasting clinical responses with immunotherapy provide a new breakthrough treatment for a variety of refractory cancer histologies, which gradually change the treatment pattern of tumors. However, although immune checkpoint inhibitor drugs are promising for achieving longer-term efficacy, their benefits in the overall population are still very low, such as low frequency of response in some common tumor types such as breast and prostate, and heterogeneity in the degree of response among different tumor lesions in the same patient, making immunotherapy with many limitations and challenges. Most patients do not respond to immunotherapy or inevitably develop resistance to treatment after a period of treatment, manifesting with primary resistance or acquired resistance who initially respond to treatment. The mechanisms of tumor immune resistance are very complex and involve multiple aspects such as genes, metabolism, inflammation, and abnormal neovascularization. Currently, many mechanisms of immunotherapy resistance have been characterized, and more continue to be uncovered. These efforts can improve the quality of medical care for cancer diagnosis and treatment, which improve the quality of life of patients, and finally lead to accurate individualized treatment. This review discusses mechanisms of cancer immunotherapy resistance including tumor-intrinsic factors and tumor-extrinsic factors.

Lipid metabolism reprograming, as a hallmark of malignancy, has received renewed interest in recent years in such areas as energy sources, cell membrane components, and signaling molecules involved in the rapid tumor growth and the adaptation to the tumor microenvironment. Lipid metabolism deregulation in cancer involves multiple aspects, including an increased lipid uptake, endogenous de novo fatty acid synthesis, fatty acid oxidation, and cholesterol accumulation, thereby promoting tumor growth and progression. Recent advances in the understanding of specific metabolic alterations in cancer reveal novel pathogenesis mechanisms and a growing number of drugs targeting lipid metabolism have been applied in anti-tumor therapy. Thus, this review discusses the lipid metabolic landscape of cancers and the interplay with oncogenic signaling, and summarizes potential therapeutic targets to improve the therapeutic efficiency in cancer patients, in order to provide more reference and thinking for the treatment of lipid metabolism of cancer patients.

T cells play important roles in anti-tumor immunity. Emerging evidence has revealed that distinct metabolic changes impact the activation and differentiation of T cells. Tailoring immune responses by manipulating cellular metabolic pathways and the identification of new targets may provide new options for cancer immunotherapy. In this review, we focus on recent advances in the metabolic reprogramming of different subtypes of T cells and T cell functions. We summarize how metabolic pathways accurately regulate T cell development, differentiation, and function in the tumor microenvironment. Because of the similar metabolism in activated T cells and tumor cells, we also describe the effect of the tumor microenvironment on T cell metabolism reprogramming, which may provide strategies for maximal anti-cancer effects and enhancing the immunity of T cells. Thus, studies of T lymphocyte metabolism can not only facilitate the basic research of immune metabolism, but also provide potential targets for drug development and new strategies for clinical treatment of cancer.

Infertility is a common complication in diabetic men, mainly due to the loss of germ cells by apoptotic cell death. However, effective and safe approaches to prevent diabetic induction of testicular apoptosis for diabetic patients have not been available. Resveratrol (RSV), a group of compounds called polyphenols from plants, has been indicated its promising used clinically for cancers and cardiovascular diseases. Therefore, the present study aimed determining whether RSV attenuates type 1 diabetes (T1D)-induced testicular apoptotic cell death in a mouse model. We found that testicular apoptosis and oxidative stress levels were significantly higher in T1D mice than control mice. In addition, the phosphorylation level of metabolism-related Akt and GSK-3β was downregulated and Akt negative regulators PTEN, PTP1B and TRB3 were upregulated in the T1D group. These effects were partially prevented by RSV treatment. Nrf2 and its downstream genes, such as NQO-1, HO-1, SOD, catalase and metallothionein were significantly upregulated by RSV treatment. In addition, RSV-induced Nrf2 activation was found due to Keap1 degradation, mainly reliant on p62 that functions as an adaptor protein during autophagy. These results indicate that the attenuation of T1D-induced testicular oxidative stress and apoptosis by RSV treatment was mainly related to Akt-mediated Nrf2 activation via p62-dependent Keap1 degradation.

Paclitaxel-loaded PLGA nanoparticles may be considered a promising drug delivery system to eradicate hypoxic tumor cells.

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The study may provide a new combination of cytotoxic drugs for HCC chemotherapy.

The CRISPR-associated Cas9 system can modulate disease-causing alleles both in vivo and ex vivo, raising the possibility of therapeutic genome editing. In addition to gene targeting, epigenetic modulation by the catalytically inactive dCas9 may also be a potential form of cancer therapy. Granulin (GRN), a potent pluripotent mitogen and growth factor that promotes cancer progression by maintaining self-renewal of hepatic stem cancer cells, is upregulated in hepatoma tissues and is associated with decreased tumor survival in patients with hepatoma. We synthesized a group of dCas9 epi-suppressors to target GRN by tethering the C terminus of dCas9 with three epigenetic suppressor genes: DNMT3a (DNA methyltransferase), EZH2 (histone 3 lysine 27 methyltransferase), and KRAB (the Krüppel-associated box transcriptional repression domain). In conjunction with guide RNAs (gRNAs), the dCas9 epi-suppressors caused significant decreases in GRN mRNA abundance in Hep3B hepatoma cells. These dCas9 epi-suppressors initiated de novo CpG DNA methylation in the GRN promoter, and they produced histone codes that favor gene suppression, including decreased H3K4 methylation, increased H3K9 methylation, and enhanced HP1a binding. Epigenetic knockdown of GRN led to the inhibition of cell proliferation, decreased tumor sphere formation, and reduced cell invasion. These changes were achieved at least partially through the MMP/TIMP pathway. This study thus demonstrates the potential utility of using dCas9 epi-suppressors in the development of epigenetic targeting against tumors.