Background: Combination of chemotherapy and immune checkpoint inhibitor therapy has greatly improved the anticancer effect on multiple malignancies. However, the efficiency on triple-negative breast cancer (TNBC) is limited, since most patients bear “cold” tumors with low tumor immunogenicity. Doxorubicin (DOX), one of the most effective chemotherapy agents, can induce immunogenic cell death (ICD) and thus initiating immune response. Methods: In this study, to maximize the ICD effect induced by DOX, chitosan and cell-penetrating peptide (R6F3)-modified nanoparticles (PNPs) loaded with ginsenoside Rg3 (Rg3) were fabricated using the self-assembly technique, followed by co-encapsulation with DOX based on thermo-sensitive hydrogel. Orthotopic tumor model and contralateral tumor model were established to observe the antitumor efficacy of the thermo-sensitive hydrogel combined with anti-PD-L1 immunotherapy, besides, the biocompatibility was also evaluated by histopathological. Results: Rg3-PNPs strengthened the immunogenic cell death (ICD) effect induced by DOX. Moreover, the hydrogel co-loading Rg3-PNPs and DOX provoked stronger immune response in originally nonimmunogenic 4T1 tumors than DOX monotherapy. Following combination with PD-L1 blocking, substantial antitumor effect was achieved due to the recruitment of memory T cells and the decline of adaptive PD-L1 enrichment. Conclusion: The hydrogel encapsulating DOX and highly permeable Rg3-PNPs provided an efficient strategy for remodeling immunosuppressive tumor microenvironment and converting immune “cold” 4T1 into “hot” tumors.

Oxaliplatin‐induced peripheral neuropathy (OIPN) is a common and dose‐limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high‐affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research.

Metabolic reprogramming is a vital hallmark of cancer, and it provides the necessary energy and biological materials to support the continuous proliferation and survival of tumor cells. NR4A1 is belonging to nuclear subfamily 4 (NR4A) receptors. NR4A1 plays diverse roles in many tumors, including melanoma, colorectal cancer, breast cancer, and hepatocellular cancer, to regulate cell growth, apoptosis, metastasis. Recent reports shown that NR4A1 exhibits unique metabolic regulating effects in cancers. This receptor was first found to mediate glycolysis via key enzymes glucose transporters (GLUTs), hexokinase 2 (HK2), fructose phosphate kinase (PFK), and pyruvate kinase (PK). Then its functions extended to fatty acid synthesis by modulating CD36, fatty acid-binding proteins (FABPs), sterol regulatory element-binding protein 1 (SREBP1), glutamine by Myc, mammalian target of rapamycin (mTOR), and hypoxia-inducible factors alpha (HIF-1α), respectively. In addition, NR4A1 is involving in amino acid metabolism and tumor immunity by metabolic processes. More and more NR4A1 ligands are found to participate in tumor metabolic reprogramming, suggesting that regulating NR4A1 by novel ligands is a promising approach to alter metabolism signaling pathways in cancer therapy. Basic on this, this review highlighted the diverse metabolic roles of NR4A1 in cancers, which provides vital references for the clinical application.

Background: To identify the association between diabetes mellitus (DM) and the risk of chemotherapy-induced peripheral neuropathy (CIPN) through a systematic review and meta-analysis. Methods: An electronic literature search was conducted in PubMed, Embase, Web of Science, the Wanfang database, the VIP Journals database (CQVIP), the China National Knowledge Infrastructure (CNKI) database, and the China Biology Medicine database (Sinomed) between January 2010 and January 2021. Articles were included if they investigated CIPN and DM. Stata 15.1 was used to analyze the data. Results: We examined 8923 cancer patients from 25 studies comprising 9 cohort studies and 16 case–control studies. Meta-analysis showed that there was a statistically significant positive correlation between DM and CIPN (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.38–1.85, P < 0.001). Egger’s test (P = 0.824) showed no evidence of publication bias. The positive associations did not significant differ by study type, study quality, evaluation instrument, and type of antineoplastic drug. Omission of any single study had little effect on the combined risk estimate. Little evidence of heterogeneity was observed. Conclusion: This meta-analysis provides evidence of a significant positive association between DM and risk of CIPN. Furthermore, a more detailed evaluation is warranted for cancer patients with diabetes when they are treated with antineoplastic drugs that have the potential to cause peripheral neuropathy.

IL-2-based therapy is a promising tool to treat colorectal cancer, but drug resistance always occurs in clinical practice. Mitochondrial fission is a novel target to modulate cancer development and progression. The aim of our study is to explore the effect of IL-2 combined with Tan IIA on SW480 colorectal cancer cell apoptosis in vitro and to determine whether IL-2/Tan IIA cotreatment could reduce SW480 cell viability via activating mitochondrial fission. The results indicated that Tan IIA increased IL-2-mediated cell death in SW480 colorectal cancer cells, and this effect was also accompanied with a reduction in cell proliferation. Functional investigations demonstrated that Tan IIA/IL-2 cotreatment enhanced INF2-related mitochondrial fission. Excessive mitochondrial division induced mitochondrial oxidative stress, mitochondrial energy metabolism disorder and mitochondrial apoptosis in SW480 cells. Inhibition of mitochondrial fission attenuated the antitumor effect of Tan IIA/IL-2 cotreatment on SW480 cell apoptosis. Further, we demonstrated that Tan IIA/IL-2 combination therapy controlled INF2-related mitochondrial fission via the Mst1-Hippo pathway. Moreover, Mst1 knockdown abrogated Tan IIA/IL-2-activated mitochondrial fission. Altogether, our results demonstrated that Tan IIA enhances the therapeutic efficiency of IL-2-mediated SW480 colorectal cancer cell apoptosis via promoting INF2-related mitochondrial fission and activating the Mst1-Hippo pathway.