Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one of the most significant biological events in cancer progression. Cancer cells generally represent a higher oxidant level, which suggests a dual therapeutic strategy by regulating redox status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, pro-oxidant therapy exhibits a great anti-cancer capability, attributing to a higher oxidant accumulation within cancer cells, whereas antioxidant therapy to restore redox homeostasis has been claimed to fail in several clinical practices. Targeting the redox vulnerability of cancer cells by pro-oxidants capable of generating excessive reactive oxygen species (ROS) has surfaced as an important anti-cancer strategy. However, multiple adverse effects caused by the indiscriminate attacks of uncontrolled drug-induced OS on normal tissues and the drug-tolerant capacity of some certain cancer cells greatly limit their further applications. Herein, we review several representative oxidative anti-cancer drugs and summarize their side effects on normal tissues and organs, emphasizing that seeking a balance between pro-oxidant therapy and oxidative damage is of great value in exploiting next-generation OS-based anti-cancer chemotherapeutics.

Extrahepatic cholangiocarcinoma (EHCC) is a refractory malignancy with poor prognosis due to its early invasion, metastasis and recurrence after operation. Therefore, understanding the mechanisms of invasion and metastasis is the key to the development of new and effective therapeutic strategies for EHCC. In the present study we demonstrated that miR-221 promoted EHCC invasion and metastasis through targeting PTEN and formed a positive feedback loop with β-catenin/c-Jun signaling pathway. We found miR-221 was upregulated in EHCC specimens and CC cell lines. Moreover, miR-221 was found strongly associated with the metastasis and prognosis of EHCC patients. The expression of PTEN was downregulated in EHCC patients and CC cell lines, and was further demonstrated as one of the downstream targets of miR-221. In addition, our data indicated that β-catenin activated miR-221 through c-jun, while miR-221 enhanced β-catenin signaling induced-epithelial-mesenchymal transition (EMT) by targeting PTEN, hence forming a positive feedback loop in EHCC cell lines. In conclusion, our results suggested that miR-221 promotes EMT through targeting PTEN and forms a positive feedback loop with β-catenin/c-Jun signaling pathway in EHCC.

The study aimed to investigate the risk factors of postpancreatectomy hemorrhage (PPH) after pancreaticoduodenectomy (PD). A retrospective analysis of 423 patients who underwent PD between January 2008 and January 2014 was conducted. The overall incidence and all-cause mortality of PPH were 9.9% (42/423) and 2.1% (9/423), respectively. Independent risk factors of early PPH were revascularization (odds ratio (OR) = 6.786; 95% confidence interval (95% CI): 1.785–25.792; P=0.005), history of abdominal surgery (OR = 5.009; 95% CI: 1.968–12.749; P=0.001), and preoperative albumin levels (OR = 4.863; 95% CI: 1.962–12.005; P=0.001). Independent risk factors of late PPH included postoperative pancreatic leakage (OR = 4.696; 95% CI: 1.605–13.740; P=0.005), postoperative biliary fistula (OR = 6.096; 95% CI: 1.575–23.598; P=0.009), postoperative abdominal infection (OR = 4.605; 95% CI: 1.108–19.144; P=0.036), revascularization (OR = 9.943; 95% CI: 1.900–52.042; P=0.007), history of abdominal surgery (OR = 8.790; 95% CI: 2.779–27.806; P<0.001), and preoperative albumin levels (OR = 5.563; 95% CI: 1.845–16.776; P=0.002).

Background: Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemo-resistance remaining a major obstacle in CRC treatment. Notably, the imbalance of redox homeostasis-mediated ferroptosis and the modulation of hypoxic tumor microenvironment are regarded as new entry points for overcoming the chemo-resistance of CRC. Methods: Inspired by this, we rationally designed a light-activatable oxygen self-supplying chemo-photothermal nanoplatform by co-assembling cisplatin (CDDP) and linoleic acid (LA)-tailored IR820 via enhanced ferroptosis against colorectal cancer chemo-resistance. In this nanoplatform, CDDP can produce hydrogen peroxide in CRC cells through a series of enzymatic reactions and subsequently release oxygen under laser-triggered photothermal to alleviate hypoxia. Additionally, the introduced LA can add exogenous unsaturated fatty acids into CRC cells, triggering ferroptosis via oxidative stress-related peroxidized lipid accumulation. Meanwhile, photothermal can efficiently boost the rate of enzymatic response and local blood flow, hence increasing the oxygen supply and oxidizing LA for enhanced ferroptosis. Results: This nanoplatform exhibited excellent anti-tumor efficacy in chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models. Conclusions: Taken together, this nanoplatform provides a promising paradigm via enhanced ferroptosis and alleviated hypoxia tumor microenvironment against CRC chemo-resistance. Graphical

Immunotherapy represents a transformative advance in cancer treatment; however, its efficacy in head and neck cancer (HNC) remains constrained by tumor cell stemness and profound immunosuppression within the tumor microenvironment (TME). Overcoming these barriers necessitates innovative strategies to simultaneously eradicate stem-like populations and reprogram the TME. We engineered a tumor-targeted polymer prodrug nanoplatform, Biotin@P-Cur/T780 NPs, integrating disulfide-linked polycurcumin (P-Cur) and the photothermal agent T780. DSPE-PEG-Biotin surface functionalization enables active tumor targeting. The nanoplatform exploits high intratumoral glutathione (GSH) to trigger disassembly, releasing curcumin monomers and T780. This elicits dual GSH depletion and reactive oxygen species (ROS) amplification, inducing ROS-mediated apoptosis and ferroptosis. Concurrently, localized near-infrared irradiation activates T780, synergizing photothermal (PTT) and photodynamic (PDT) therapies to intensify immunogenic cell death (ICD). The Biotin@P-Cur/T780 NPs potently suppressed tumor cell stemness in vitro and in vivo. ROS/ferroptosis-driven ICD, amplified by PTT/PDT, reversed TME immunosuppression, enhancing dendritic cell maturation and cytotoxic T lymphocyte infiltration. This multimodal mechanism significantly inhibited primary tumor growth and metastasis in HNC models, while extending survival. Our prodrug nanoplatform overcomes key resistance mechanisms in HNC by coordinately targeting stemness, inducing dual apoptosis/ferroptosis, and potentiating ICD through PDT/PTT-enhanced immunomodulation. This strategy provides a potent combinatorial approach to augment immunotherapy efficacy in refractory tumors.

Appendiceal mucinous neoplasm (AMN) is extremely rare. Since the disease does not manifest a characteristic profile of clinical symptoms, it is easy to misdiagnose and still difficult to diagnose without operation. Here, we report a case of low-grade AMN (LAMN) and summarize its clinical features, diagnosis, and treatment. A 63-year-old postmenopausal woman presented with a history of right lower abdominal mass. The patient underwent laparotomy, which showed an appendiceal mucocele originating from the apex of the appendix, and a simple appendectomy was performed. The subsequent histological assessment identified an LAMN with no lymph node involvement and negative surgical margin. The patient received six cycles of chemotherapy after surgery, and to date, more than a year after the surgery, the patient remains in good health. A unified, standardized, detailed, and accurate pathological diagnosis is needed for LAMN, to facilitate selection of an appropriate surgical plan. In addition, the surgeon should record the details of the tumors in the surgical records in order to facilitate follow-up after surgery.