Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.

Demanded as an essential trace element that supports cell growth and basic functions, iron can be harmful and cancerogenic though. By exchanging between its different oxidized forms, iron overload induces free radical formation, lipid peroxidation, DNA, and protein damages, leading to carcinogenesis or ferroptosis. Iron also plays profound roles in modulating tumor microenvironment and metastasis, maintaining genomic stability and controlling epigenetics. in order to meet the high requirement of iron, neoplastic cells have remodeled iron metabolism pathways, including acquisition, storage, and efflux, which makes manipulating iron homeostasis a considerable approach for cancer therapy. Several iron chelators and iron oxide nanoparticles (IONPs) has recently been developed for cancer intervention and presented considerable effects. This review summarizes some latest findings about iron metabolism function and regulation mechanism in cancer and the application of iron chelators and IONPs in cancer diagnosis and therapy.

Tumor associated macrophages (TAMs) play an important role in tumorigenesis, development and anti-cancer drug therapy. However, very few epigenetic compounds have been elucidated to affect tumor growth by educating TAMs in the tumor microenvironment (TME). Herein, we identified that EZH2 performs a crucial role in the regulation of TAMs infiltration and protumoral polarization by interacting with human breast cancer (BC) cells. We showed that EZH2 inhibitors-treated BC cells induced M2 macrophage polarization in vitro and in vivo, while EZH2 knockdown exhibited the opposite effect. Mechanistically, inhibition of EZH2 histone methyltransferase alone by EZH2 inhibitors in breast cancer cells could reduce the enrichment of H3K27me3 on CCL2 gene promoter, elevate CCL2 transcription and secretion, contributing to the induction of M2 macrophage polarization and recruitment in TME, which reveal a potential explanation behind the frustrating results of EZH2 inhibitors against breast cancer. On the contrary, EZH2 depletion led to DNA demethylation and subsequent upregulation of miR-124-3p level, which inhibited its target CCL2 expression in the tumor cells, causing arrest of TAMs M2 polarization. Taken together, these data suggested that EZH2 can exert opposite regulatory effects on TAMs polarization through its enzymatic or non-enzymatic activities. Our results also imply that the effect of antitumor drugs on TAMs may affect its therapeutic efficacy, and the combined application with TAMs modifiers should be warranted to achieve great clinical success.

Son of sevenless homolog 1 (SOS1) is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR–ABL in leukemogenesis. Despite this, small-molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS-mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 proteolysis targeting chimera (PROTAC) SIAIS562055, which was designed by connecting a CRBN ligand to an analog of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior antiproliferative activity compared with small-molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR–ABL–positive CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR–ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR–ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary samples from patients with CML. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR–ABL–harboring leukemia. Significance: The PROTAC SIAIS562055 sustainably degrades SOS1 and inhibits downstream ERK signaling, showing strong antiproliferative activity and synergistic effects with KRAS inhibitors in KRAS-mutant cancers and BCR–ABL inhibitors in chronic myeloid leukemia.

Selective inhibition of the transcription elongation factor (P‐TEFb) complex represents a promising approach in cancer therapy, yet CDK9 inhibitors (CDK9i) are currently limited primarily to certain hematological malignancies. Herein, while initial responses to CDK9‐targeted therapies are observed in vitro across various KRAS‐mutant cancer types, their efficacy is far from satisfactory in nude mouse xenograft models. Mechanistically, CDK9 inhibition leads to compensatory activation of ERK‐MYC signaling, accompanied by the recovery of proto‐oncogenes, upregulation of immediate early genes (IEGs), stimulation of the complement C1r‐C3‐C3a cascade, and induction of tumor immunosuppression. The “paradoxical” regulation of PP2Ac activity involving the CDK9/Src interplay contributes to ERK phosphorylation and pause‐release of RNA polymerase II (Pol II). Co‐targeting of CDK9 and KRAS/MAPK signaling pathways eliminates ERK‐MYC activation and prevents feedback activation mediated by receptor tyrosine kinases, leading to more effective control of KRAS‐mutant cancers and overcoming KRASi resistance. Moreover, modulating the tumor microenvironment (TME) by complement system intervention enhances the response to CDK9i and potently suppresses tumor growth. Overall, the preclinical investigations establish a robust framework for conducting clinical trials employing KRASi/SOS1i/MEKi or immunomodifiers in combination with CDK9i to simultaneously target cancer cells and their crosstalk with the TME, thereby yielding improved responses in KRAS‐mutant patients.

Despite the rapid development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in recent decades, resistance remains a significant challenge in managing advanced non-small cell lung cancer (NSCLC). Elucidating the mechanisms underlying EGFR-TKI resistance and developing novel strategies are therefore crucial. In this study, we investigated the role of polo-like kinase 1 (PLK1) in EGFR-mutant NSCLC and evaluated the therapeutic potential of combining EGFR-TKIs with PLK1 inhibitors. We demonstrated that high PLK1 expression correlates with STAT3 signaling activation and decreased survival probability in EGFR-mutant NSCLC patients. Subsequent studies revealed that PLK1 inhibitors effectively reversed the activation of STAT3 induced by EGFR-TKIs. When used in combination with EGFR-TKIs, they promoted cell apoptosis, inhibited cell proliferation in vitro, and induced tumor regression in animal models. Mechanistically, our data demonstrated that PLK1 regulated STAT3 activity through protein-protein interactions and JAK1-mediated phosphorylation, while STAT3 reciprocally regulated PLK1 transcription, establishing a positive feedback loop between these signaling molecules. This PLK1/STAT3 loop was further reinforced by FGFR1 upregulation and directly linked to EGFR-TKI resistance. Targeting this axis with combinatorial inhibitors exerted synergistic anti-tumor effects, suppressing proliferation and migration in osimertinib-resistant models. In conclusion, concurrent inhibition of EGFR and FGFR1/STAT3/PLK1 signaling pathways provides a promising therapeutic strategy for NSCLC patients with EGFR mutations, enhancing efficacy and overcoming resistance.