Small-molecule Smac mimetics are being developed as a novel class of anticancer drugs. Recent studies have shown that Smac mimetics target cellular inhibitor of apoptosis protein (cIAP)-1/2 for degradation and induce tumor necrosis factor-α (TNFα)–dependent apoptosis in tumor cells. In this study, we have investigated the mechanism of action and therapeutic potential of two different types of novel Smac mimetics, monovalent SM-122 and bivalent SM-164. Our data showed that removal of cIAP-1/2 by Smac mimetics or small interfering RNA is not sufficient for robust TNFα-dependent apoptosis induction, and X-linked inhibitor of apoptosis protein (XIAP) plays a critical role in inhibiting apoptosis induction. Although SM-164 is modestly more effective than SM-122 in induction of cIAP-1/2 degradation, SM-164 is 1,000 times more potent than SM-122 as an inducer of apoptosis in tumor cells, which is attributed to its much higher potency in binding to and antagonizing XIAP. SM-164 induces rapid cIAP-1 degradation and strong apoptosis in the MDA-MB-231 xenograft tumor tissues and achieves tumor regression, but has no toxicity in normal mouse tissues. Our study provides further insights into the mechanism of action for Smac mimetics and regulation of apoptosis by inhibitor of apoptosis proteins. Furthermore, our data provide evidence that SM-164 is a promising new anticancer drug for further evaluation and development. [Cancer Res 2008;68(22):9384–93]

We report herein the structure-based design of a class of conformationally constrained, potent, cell-permeable small-molecule inhibitors to target the SH2 domain in STAT3. Compound 11 (CJ-1383) binds to STAT3 with a K_i value of 0.95 μM, dose-dependently inhibits cellular STAT3 signaling and cancer cell growth, and induces apoptosis in the MDA-MB-468 cancer cell line with constitutively activated STAT3.

Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity in various experimental models. Its clinical applications in cancer treatment, however, have been hampered due in part to its relatively moderate activity as a single agent. In this study, we performed a high-throughput screening of the FDA-approved drug library for clinical compounds that potentiate the anticancer activity auranofin, and unexpectedly identified an anti-inflammatory drug celecoxib (CE) that potently enhanced the therapeutic activity of AF in vitro and in vivo. Mechanistically, AF/CE combination induced severe oxidative stress that caused ROS-mediated inhibition of hexokinase (HK) and a disturbance of mitochondrial redox homeostasis, resulting in a significant decrease of ATP generation. The CE-induced ROS increase together with AF-medicated inhibition of thioredoxin reductase cause a shift of Trx2 to an oxidized state, leading to degradation of MTCO2 and dysfunction of the electron transport chain. Our study has identified a novel drug combination that effectively eliminates cancer cells in vivo. Since AF and CE are FDA-approved drugs that are currently used in the clinic, it is feasible to translate the findings of this study into clinical applications for cancer treatment.

The peritumoural adipose tissue (PAT) is a key contributor to cancer therapy resistance, yet its role in regulating ferroptosis remains unclear. Here we demonstrate that PAT confers ferroptosis resistance to cancer cells by upregulating ferritin (FTH1/FTL) and sequestering intracellular iron. PAT-derived kynurenine (KYN) was identified as the principal mediator. KYN is taken up by cancer cells and metabolized to 3-hydroxykynurenine, which directly binds to nuclear receptor coactivator 4 (NCOA4). This interaction inhibits NCOA4-mediated ferritinophagy, preventing ferritin degradation and limiting the free iron pool required for ferroptosis. In murine models, pharmacological inhibition of the KYN pathway synergized with PD-1 blockade to overcome ferroptosis resistance and suppress tumour progression. These findings reveal a PAT–KYN–ferritinophagy axis that promotes ferroptosis resistance, highlighting the potential of targeting adipose–tumour cross-talk to enhance immunotherapy in PAT-associated tumours.

Clinical outcomes are often suboptimal in patients with colorectal cancer treated with neoadjuvant chemotherapy (NAC). A key determinant of the response to NAC is the functional state of tumor-infiltrating immune cells. Understanding how NAC reshapes the immunologic landscape will be essential for refining patient stratification and identifying effective combination treatment strategies. In this study, we analyzed paired samples before and after NAC treatment by single-cell RNA sequencing (scRNA-seq), revealing that NAC treatment significantly reshaped the immune microenvironment. Tumors from NAC nonresponders featured increased immunosuppressive M2-like macrophage infiltration, which correlated with elevated phosphatidylserine-specific phospholipase A1 (PLA1A). Mechanistically, PLA1A hydrolyzed phosphatidylserine (PS) exposed by chemotherapy to elevate lysophosphatidylserine (LysoPS), which activated the P2ry10 receptor and downstream signaling to promote M2-like macrophage polarization. Importantly, pharmacologic inhibition of PLA1A by cilengitide synergized with chemoimmunotherapy to suppress tumor progression in murine models. Clinically, high plasma PLA1A levels negatively correlated with responses to chemoimmunotherapy. Collectively, these findings reveal a chemotherapy-driven metabolic axis that induces an immunosuppressive milieu by increasing LysoPS release. This axis highlights PLA1A as a therapeutic target to mitigate immunosuppression and improve chemoimmunotherapy efficacy. Significance: Chemotherapy-resistant colorectal cancer elevates PLA1A to induce anti-inflammatory macrophage polarization, supporting the potential of PLA1A as a therapeutic target for enhancing chemoimmunotherapy efficacy and as a biomarker of treatment response.