Vascular disrupting agents (VDAs) have great potential for cancer treatment. Poly(l‐glutamic acid)‐combretastatin A4 conjugate (PLG‐CA4) is a novel class of VDAs. Though it has notable antitumor activity, it can induce host immune responses that promote tumor growth. Here, PLG‐CA4 induces the polarization of tumor‐associated macrophages (TAMs) toward the M2‐like phenotype in 4T1 metastatic breast cancer (Control 30% vs PLG‐CA4 53%; p < 0.05). Compared to the monotherapy of PLG‐CA4, inhibition of phosphoinositide 3‐kinase gamma (PI3Kγ) attenuates the immunosuppressive effect of PLG‐CA4 treatment by decreasing the number of M2‐like TAMs (2.0 × 10⁴ to 1.5 × 10⁴ per tumor) and potential enhancement of cytotoxic T lymphocyte (3.0 × 10⁴ to 5.7 × 10⁴ per tumor). Importantly, PI3Kγ inhibitor synergizing with PLG‐CA4 significantly extends the mean survival time from 52 days in monotherapy‐treated mice to 61.8 days. Additionally, the combination of PLG‐CA4 and PI3Kγ inhibitor improves the tumor therapeutic effect of NLG919, an inhibitor of immune checkpoint indoleamine 2,3‐dioxygenase (IDO). As far as it is known, this is the first demonstrated study that VDAs induce the reshaping of macrophages to the M2‐like phenotype. The findings also indicate a potential therapeutic strategy of the combination VDAs with an accurate immune modifier in the tumor to reverse the immune resistance.

The tumor microenvironment (TME) plays a key role in promoting the initiation and progression of tumors, leading to chemoradiotherapy resistance and immunotherapy failure. Targeting of the TME is a novel anti-tumor therapeutic approach and is currently a focus of anti-tumor research. Panax ginseng C. A. Meyer (ginseng), an ingredient of well-known traditional Asia medicines, exerts beneficial anti-tumor effects and can regulate the TME. Here, we present a systematic review that describes the current status of research efforts to elucidate the functions and mechanisms of ginseng active components (including ginsenosides and ginseng polysaccharides) for achieving TME regulation. Ginsenosides have variety effects on TME, such as Rg3, Rd and Rk3 can inhibit tumor angiogenesis; Rg3, Rh2 and M4 can regulate the function of immune cells; Rg3, Rd and Rg5 can restrain the stemness of cancer stem cells. Ginseng polysaccharides (such as red ginseng acidic polysaccharides and polysaccharides extracted from ginseng berry and ginseng leaves) can regulate TME mainly by stimulating immune cells. In addition, we propose a potential mechanistic link between ginseng-associated restoration of gut microbiota and the tumor immune microenvironment. Finally, we describe recent advances for improving ginseng efficacy, including the development of a nano-drug delivery system. Taken together, this review provides novel perspectives on potential applications for ginseng active ingredients as anti-cancer adjuvants that achieve anti-cancer effects by reshaping the tumor microenvironment.

Anti-programmed cell death protein 1 (PD-1) therapy has shown promising efficacy in hepatocellular carcinoma (HCC), but its response rates in advanced HCC are lower than 20%. A critical reason for this is the imbalance between CD8⁺ T cells and tumor burden. Here, a novel concept of vascular disruption and normalization dependent on a polymeric vascular disrupting agent (VDA) poly (_L-glutamic acid)-graft-methoxy poly (ethylene glycol)/combretastatin A4 (CA4-NPs) + a vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) inhibitor DC101 is applied to improve anti-PD-1 therapy, wherein CA4-NPs reduce tumor burden and DC101 simultaneously increases the number of intratumoral CD8⁺ T cells, successfully regulating the abovementioned imbalance in an H22 tumor model.

The phosphoinositide 3-kinase (PI3K) pathway shows frequent aberrant alterations and pathological activation in breast cancer cells. While PI3K inhibitors have not achieved expectant therapeutic efficacy in clinical trials, and several studies provide promising combination strategies to substantially maximize therapeutic outcomes. Besides its direct impact on regulating cancer cells survival, PI3K inhibitors are also demonstrated to have an immunomodulatory impact based on the tumor microenvironment. Inhibition of the leukocyte-enriched PI3K isoforms may break immune tolerance and restore cytotoxic T cell activity by reprogramming the tumor microenvironment. In addition, PI3K inhibitors have pleiotropic effects on tumor angiogenesis and even induce tumor vascular normalization. In this review, we discuss the mechanism of PI3K inhibitor suppression of breast cancer cells and modulation of the tumor microenvironment in order to provide further thoughts for breast cancer treatment.

ATPase/Helicases and nucleases play important roles in homologous recombination repair (HRR). Many of the mechanistic details relating to these enzymes and their function in this fundamental and complicated DNA repair process remain poorly understood in archaea. Here we employed Sulfolobus islandicus, a hyperthermophilic archaeon, as a model to investigate the in vivo functions of the ATPase/helicase HerA, the nuclease NurA, and their associated proteins Mre11 and Rad50. We revealed that each of the four genes in the same operon, mre11, rad50, herA, and nurA, are essential for cell viability by a mutant propagation assay. A genetic complementation assay with mutant proteins was combined with biochemical characterization demonstrating that the ATPase activity of HerA, the interaction between HerA and NurA, and the efficient 5′-3′ DNA end resection activity of the HerA-NurA complex are essential for cell viability. NurA and two other putative HRR proteins: a PIN (PilT N-terminal)-domain containing ATPase and the Holliday junction resolvase Hjc, were co-purified with a chromosomally encoded N-His-HerA in vivo. The interactions of HerA with the ATPase and Hjc were further confirmed by in vitro pull down. Efficient 5′-3′ DNA end resection activity of the HerA-NurA complex contributes to necessity of HerA and NurA in Sulfolobus, which is crucial to yield a 3′-overhang in HRR. HerA may have additional binding partners in cells besides NurA.