Dual‐Interface Nanopore Array Sensor Revealing the Synergistic Oscillations of Lactate Efflux in Cancer Cells

Abstract

ABSTRACT Lactate is a key substrate and signaling molecule in tumor metabolism. Its efflux from cancer cells acidifies the tumor microenvironment and reflects the energy metabolic states. Clarifying the lactate efflux is crucial for understanding how cancer cells rapidly adjust energy metabolism and cooperatively adapt to stress. However, the endogenous reactive oxygen species (ROS) of cancer cells severely interfere with oxidase‐based lactate sensor signals and hinder quantitative analysis of lactate efflux. To address this challenge, we developed a dual‐interface nanopore array sensor (DINAS) that integrates an anti‐ROS interface and a lactate sensing interface. When cultured on the sensor, the cancer cells release ROS and lactate that diffuse along the nanopores: the outer anti‐ROS interface electrochemically removes ROS, while the inner sensing interface monitors lactate efflux. Using this dual‐interface sensor design, we disclosed that the drug‐induced lactate efflux exhibits a time‐dependent “rise‐then‐fall” behavior, reflecting the energy metabolic reprogramming. Moreover, we unexpectedly observed a synergistic oscillation in lactate efflux at the cell population level. This oscillation might indicate a connexins‐related coordination of lactate homeostasis between a population of cancer cells, and its discovery may provide new strategies for future precision anticancer therapies targeting the regulating ability of lactate metabolism.