Nanodrug delivery systems have revolutionized tumor therapy like never before. By overcoming the complexity of the tumor microenvironment (TME) and bypassing drug resistance mechanisms, nanotechnology has shown great potential to improve drug efficacy and reduce toxic side effects. This review examines the impact of the TME on drug resistance and recent advances in nanomedicine delivery systems to overcome this challenge. Characteristics of the TME such as hypoxia, acidity, and high interstitial pressure significantly reduce the effectiveness of chemotherapy and radiotherapy, leading to increased drug resistance in tumor cells. Then, this review summarizes innovative nanocarrier designs for these microenvironmental features, including hypoxia-sensitive nanoparticles, pH-responsive carriers, and multifunctional nanosystems that enable targeted drug release and improved drug penetration and accumulation in tumors. By combining nanotechnology with therapeutic strategies, this review offers a novel perspective by focusing on the innovative design of nanocarriers that interact with the TME, a dimension often overlooked in similar reviews. We highlight the dual role of these nanocarriers in therapeutic delivery and TME modulation, emphasize their potential to overcome drug resistance, and look at future research directions.

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor (iPDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation, macrophage polarization and DC maturation. The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

Radiotherapy (RT) is a crucial treatment modality for various solid tumors. Its antitumor effects not only depend on direct DNA damage but also involve the disruption of redox homeostasis centered around mitochondria and the activation of immune responses. Mitochondria, as a central hub for cellular energy metabolism and apoptosis signaling, serve both as the primary source of reactive oxygen species (ROS) and as key targets for ROS attack during RT. RT promotes the sustained accumulation of mitochondrial ROS (mROS) through mechanisms such as damage to the mitochondrial respiratory chain complexes, while also triggering compensatory clearance responses from antioxidant systems. The dynamic balance between these processes determines the cell’s fate. Moreover, mitochondria play a crucial regulatory role in immunogenic cell death (ICD). Damage-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA), ATP, and cytochrome c, along with ROS-mediated endoplasmic reticulum stress and calcium signaling, promote dendritic cell (DC) maturation and induce antitumor immunity. In recent years, mitochondria-based RT sensitization strategies have emerged, including small molecules that modulate mROS production or antioxidant defenses, mitochondria-targeted nanocarriers, gene-editing approaches, and bioregulatory or metabolic interventions. Most nanoplatforms, gene-editing strategies, and ICD-amplifying approaches are currently supported mainly by preclinical evidence, where they have been shown to enhance RT-induced tumor cell death, promote DAMP release, and improve antitumor immune activation. In contrast, selected metabolic or bioregulatory interventions have begun to enter early clinical evaluation, including ketogenic dietary interventions combined with immune checkpoint blockade in metastatic melanoma and renal cell carcinoma (e.g., NCT06391099 and NCT06896552), although definitive evidence of clinical benefit in combination with RT remains limited. This review systematically discusses mitochondrial mechanisms of ROS generation and clearance during RT, mitochondrial regulation of ICD pathways, and emerging mitochondria-targeted radiosensitization strategies, while emphasizing the current distinction between preclinical promise and clinical translational maturity.

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Gene therapy has been widely studied in colon cancer treatment. However, effective delivery of genes is a limitation for clinical applications. In the research, DOATP/mPEG-PLA-mPEG (DPLP) nanoparticles carrying the vesicular stomatitis virus matrix protein plasmid (pVSVMP) was used for colon cancer therapy, resulting in high transfection efficiency and expression efficiency in CT26 cells. Moreover, the DPLP-pVSVMP complex was provide with apoptosis induction and proliferation suppression of CT26 cells in vitro and can efficiently inhibit tumor growth in murine colon cancer model by inducing apoptosis, suppressing proliferation and angiogenesis. These results suggest that DPLP nanoparticles delivering pVSVMP might be a latent therapeutic avenue for colon cancer.

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