Chemoresistance and metastasis are the main obstacles to the clinical success of anticancer treatment and are responsible for most cancer deaths. Developing effective approaches to reverse chemoresistance and inhibit metastasis is essential for efficient chemotherapy. Mitochondria are important sources of cellular energy and are involved in mediating chemoresistance and driving tumor metastasis. Due to the relatively weak DNA repair capacity of mitochondria, targeting mitochondria may reverse chemoresistance and provide a paradigm for metastatic cancer treatment. Herein, exosomes (Exos) modified with integrin ligands and mitochondriotropic molecules are synthesized for encapsulating oxaliplatin (OXA) to construct a sequentially targeted and mitochondrion‐dysfunctional nanodrug (OXA@Exo‐RD). Subsequent investigations confirm that OXA@Exo‐RD targeted cancer cells and mitochondria in sequence, and OXA delivered to mitochondria lacking DNA repair mechanisms reduce the likelihood of deactivation. Furthermore, the OXA@Exo‐RD promotes the overproduction of ROS, inhibited ATP generation, and induces mitochondria‐mediated apoptosis and mitochondrial dysregulation. Finally, OXA@Exo‐RD shows the potential to inhibit the growth and metastasis of HCT116/OXA cells in vitro, which is further validated in subcutaneous and orthotopic CRC models, as well as in CRC metastasis models. Taken together, this dual‐targeting nanomedicine induces apoptosis via mitochondrial signaling pathways, providing an attractive strategy for the treatment of drug‐resistant CRC.

Colon cancer (CC) remains a primary contributor to cancer-related fatalities worldwide, driven by difficulties in early diagnosis and constrained therapeutic options. Recent studies underscore the importance of the tumor microenvironment (TME), notably tumor-associated macrophages (TAMs), in fostering malignancy progression and therapy resistance. Through their inherent plasticity, TAMs facilitate immunosuppression, angiogenic processes, metastatic spread, and drug tolerance. In contrast to M1 macrophages, which promote inflammatory and tumoricidal responses, M2 macrophages support tumor expansion and dissemination by exerting immunosuppressive and pro-angiogenic influences. Consequently, manipulating TAMs has emerged as a potential avenue to enhance treatment effectiveness. This review outlines the origins, polarization states, and functions of TAMs in CC, highlights their role in driving tumor advancement, and surveys ongoing efforts to target these cells for better patient outcomes. Emerging therapeutic strategies aimed at modulating TAM functions - including depletion strategies, reprogramming approaches that shift M2-polarized TAMs toward an M1 phenotype, and inhibition of key signaling pathways sustaining TAM-mediated immunosuppression-are currently under active investigation. These approaches hold promise in overcoming TAM - induced resistance and improving immunotherapeutic efficacy in CC.

N6-methyladenosine (m6A) is the most abundant and well-investigated internal RNA modification in eukaryotic RNAs, affecting its target gene expression by controlling RNA localization, splicing, stability, and translation. m6A modifications are regulated by m6A methyltransferase complex, demethylase, and reading proteins. Insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), a member of a conserved family of single-stranded RNA-binding proteins, has recently been identified as a vital m6A reading protein. IGF2BP1 is highly expressed in various tumors and is associated with poor prognosis and treatment resistance. Furthermore, previous studies have shown that IGF2BP1 plays critical roles in regulating various cancer hallmarks, including sustained cell proliferation, cell death resistance, activation of invasion and metastasis, deregulated cellular energetics, immune evasion, and unlocking phenotypic plasticity. IGF2BP1 could promote the expression of cancer-related genes by recognizing their m6A sites, thereby altering cell characteristics, and eventually, malignancy. Therefore, IGF2BP1 might be a potential target for tumor diagnosis and anti-tumor therapeutic strategies. This review summarizes the current knowledge on the functional roles and underlying molecular mechanisms of IGF2BP1 in regulating cancer hallmarks. Moreover, we discuss the prospects of IGF2BP1 as a potential tumor diagnosis marker, as well as a potential target for an anti-tumor therapeutic strategy.

Background: Management of the immunosuppressive tumor microenvironment (TME) is crucial for microsatellite stability (MSS) colorectal cancer (CRC), which responds poorly to immunotherapy. PIN1, a peptidyl-prolyl cis-trans isomerase that is overexpressed in human malignancies, regulates TME immunosuppression. However, its role in MSS CRC remains insufficiently explored. Methods: We divided 411 CRC patients from the TCGA-COAD database into MSS or microsatellite instability-high (MSI-H) groups and analyzed their gene expression profiles. Using smoothed t-statistic SVM, weighted correlation network analysis, and sample clustering, we identified PIN1 as a key biomarker. We assessed Pin1 expression in CRC cell lines and tissues, and conducted functional assays, in vitro co-cultures, and in vivo studies (using a Pin1 inhibitor and anti-PD-1 in CT26 subcutaneous tumor and liver metastasis mouse models) to evaluate its effects and mechanisms. Results: PIN1 was overexpressed in MSS CRC and negatively correlated with CD4+ T and CD8+ T cell infiltration. Knockdown of PIN1 in MSS CRC cells significantly reduced cell proliferation (assessed by CCK-8 assay), impaired migratory capacity (assessed via wound-healing assay), and increased the apoptotic rate (detected by flow cytometry). In CT26 mouse models, combining Pin1 inhibition with PD-1 blockade enhanced immunotherapy efficacy by reducing Treg infiltration, suppressing cancer-associated fibroblast (CAF) activity, and promoting CD8+ T cell recruitment. Mechanistically, PIN1 activated the NF-κB pathway and modulated CCL3-CCR5 signaling, which are critical for Treg migration and CAF activation. Conclusion: Our findings suggest that Pin1 reshapes the immunosuppressive TME in MSS CRC through the NF-κB-CCL3-CCR5 axis, driving CRC progression and immunotherapy resistance. This pathway presents a potential target for overcoming immunotherapy resistance in MSS CRC.

In this study, the regulation of abscisic acid (ABA) on cell growth and lipid biosynthesis was investigated under saltinduced stress in Chlorella pyrenoidosa. It is found that as suffering from only salt stress, although the lipid content of single cell was improved, the inhibitory effects of stress on cell proliferation was visible. When the algal cells were exposed to salt stress and ABA conditions, lipid productivity was increased (45.35 mg L-1 d-1) by 1.17-fold compared to that of control cells (20.91 mg L-1 d-1), and the inhibition to cell growth was relieved. Transcriptomic analysis revealed that after adding ABA, these genes involved in antioxidant activity, jasmonic acid (JA) biosynthesis, and lipid biosynthesis were upregulated. Subsequently, we observed that the levels of glutathione, total antioxidant capacity, trehalose, and JA were elevated and the levels of reactive oxygen species were reduced. This study presents an effective approach to improve lipid production in algal cells, a new mechanism on that ABA alleviates intracellular oxidative stress through JA signaling pathway was elaborated.

Tumor cells alter lipid metabolic pathways to meet their demands for energy and membrane biosynthesis. Despite its crucial role in tumor cell growth, survival, and metastasis, the mechanisms underlying tumor cell lipid metabolic reprogramming remain poorly understood. Pre-B-cell leukemia transcription factor 3 (PBX3), a member of the PBX family, could promote tumorigenesis; however, whether it is involved in tumor lipid metabolic reprogramming remains unknown. Herein, we found that PBX3 significantly promotes tumor growth by enhancing lipid accumulation in HCC cells. By assessing the effect of PBX3 on the expression levels of lipid metabolism-related genes, we found that PBX3 could positively regulate the expression of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), a rate-limiting enzyme in the cholesterol biosynthesis pathway. Mechanistically, we revealed that PBX3 could directly bind to the −167/−151 region of HMGCR promoter, thereby increasing its transcriptional activity and, subsequently, its expression level. This leads to the increase of HCC cell cholesterol biosynthesis and, eventually, to the increase of the in vivo tumorigenic potential. Collectively, our research revealed an unprecedented regulatory mechanism of cholesterol metabolism in HCC cells through PBX3 positive regulation on HMGCR expression levels. These findings provide novel insights into tumor metabolic reprogramming and uncover a previously unknown physiological function for PBX3. Moreover, these results suggest the potential of targeting PBX3 as an anti-tumor therapeutic strategy.