This perspective describes the advances in cobalt-containing compounds as anticancer agents. Cobalt, being an essential trace element, offers a less toxic alternative to traditional platinum-based anticancer drugs.

Immunogenic cell death (ICD) offers a method of stimulating the immune system to attack and remove cancer cells. We report a copper(II) complex containing a Schiff base ligand and a polypyridyl ligand, 4, capable of inducing ICD in breast cancer stem cells (CSCs). Complex 4 kills both bulk breast cancer cells and breast CSCs at sub‐micromolar concentrations. Notably, 4 exhibits greater potency (one order of magnitude) towards breast CSCs than salinomycin (an established breast CSC‐potent agent) and cisplatin (a clinically approved anticancer drug). Epithelial spheroid studies show that 4 is able to selectively inhibit breast CSC‐enriched HMLER‐shEcad spheroid formation and viability over non‐tumorigenic breast MCF10 A spheroids. Mechanistic studies show that 4 operates as a Type II ICD inducer. Specifically, 4 readily enters the endoplasmic reticulum (ER) of breast CSCs, elevates intracellular reactive oxygen species (ROS) levels, induces ER stress, evokes damage‐associated molecular patterns (DAMPs), and promotes breast CSC phagocytosis by macrophages. As far as we are aware, 4 is the first metal complex to induce ICD in breast CSCs and promote their engulfment by immune cells.

Intracellular redox modulation offers a viable approach to effectively remove cancer stem cells (CSCs), a subpopulation of tumour cells thought to be responsible for cancer recurrence and metastasis. Here we report the breast CSC potency of reactive oxygen species (ROS)-generating manganese(II)- and copper(II)-4,7-diphenyl-1,10-phenanthroline complexes bearing diclofenac, a nonsteriodial anti-inflammatory drug (NSAID), 1 and 3. Notably, the manganese(II) complex, 1, exhibits 9-fold, 31-fold, and 40-fold greater potency towards breast CSCs than 3, salinomycin (an established breast CSC-potent agent), and cisplatin (a clinically approved anticancer drug) respectively. Encouragingly, 1 displays 61-fold higher potency toward breast CSCs than normal skin fibroblast cells. Clinically relevant epithelial spheroid studies show that 1 is able to selectively inhibit breast CSC-enriched HMLER-shEcad mammosphere formation and viability (one order of magnitude) over non-tumorigenic breast MCF10A spheroids. Mechanistic studies show that 1 prompts breast CSC death by generating intracellular ROS and inhibiting cyclooxygenase-2 (COX-2) activity. The manganese(II) complex, 1, induces a greater degree of intracellular ROS in CSCs than the corresponding copper(II) complex, 3, highlighting the ROS-generating superiority of manganese(II)- over copper(II)-phenanthroline complexes. Encapsulation of 1 by biodegradable methoxy poly(ethylene glycol)-b-poly(D,L-lactic-co-glycolic) acid (PEG-PLGA) copolymers at the appropriate feed (5%, 1 NP⁵) enhances breast CSC uptake and greatly reduces overall toxicity. The nanoparticle formulation 1 NP⁵ indiscriminately kills breast CSCs and bulk breast cancer cells, and evokes a similar cellular response to the payload, 1. To the best of our knowledge, this is the first study to investigate the anti-CSC properties of managense complexes and to demonstrate that polymeric nanoparticles can be used to effectively deliver managense complexes into CSCs.