Nano-strategies for Targeting Tumor-Associated Macrophages in Cancer immunotherapy

Abstract

Tumor-associated macrophages (TAMs) are one type of the most abundant immune cells within tumor, resulting in immunosuppresive tumor microenvironment and tumor resistance to immunotherapy. Thus, targeting TAMs is a promising therapeutic strategy for boosting cancer immunotherapy. This study provides an overview of current therapeutic strategies targeting TAMs, which focus on blocking the recruitment of TAMs by tumors, regulating the polarization of TAMs, and directly eliminating TAMs using various nanodrugs, especially with a new categorization based on the specific signaling pathways, such as NF-κB, HIF-1α, ROS, STAT, JNK, PI3K, and Notch involved in their regulatory mechanism. The latest developments of nanodrugs modulating these pathways are discussed in determining the polarization of TAMs and their role in the tumor microenvironment. Despite the challenges in clinical translation and the complexity of nanodrug synthesis, the potential of nanodrugs in enhancing the effectiveness of cancer immunotherapy is worthy of expecting.

Keywords: Cancer immunotherapy; M1 polarization; Nanodrugs; Signaling pathways; Tumor-associated macrophages.

Figure 1

The polarization of macrophages. M0 macrophages can differentiate into either M1 or M2 macrophages when stimulated by different cytokines. M1 macro-phages are known for their involvement in inflammatory responses and have both proinflammatory and anti-tumor effects. In contrast, M2 macrophages are commonly found in the immunosuppresive microenvironment, where they exert an anti-inflammatory effect and contribute to tumor growth and metastasis.

Figure 2

Current therapeutic strategies for targeting TAMs with nanodrugs. Through blocking tumor recruitment of TAMs, depleting/suppressing TAMs, and reprogramming TAMs, the goal is to reshape the TME and enhance the immune response against cancer. Nanodrugs have the potential to precisely deliver and release therapeutic agents, offering a promising approach to enhance the effectiveness of TAM-targeting immunotherapies while minimizing side effects.

Figure 3

Cellular signaling networks in TAMs. The cellular signaling networks within TAMs are vital for regulating their polarization. Signaling pathways such as NF-κB, HIF-1α, ROS, STAT, JNK, PI3K, and Notch play a critical role in determining the direction of TAM polarization. These pathways can function independently or interact with each other to influence TAM polarization. Consequently, they present potential targets for nanodrugs in cancer immunotherapy focused on TAMs.

Figure 4

Schematic illustration of the interaction between nanobiointerfaces and TAM repolarization in situ by SNs elasticity. The stiff and soft SNs interact with the macrophage cell membrane, and the soft SNs activate Piezo1 through slight plasma membrane deformation, further inducing Ca²⁺ influx and activating the NF-κB pathway. The soft SNs can penetrate the intratumoral hypoxic regions and reprogram TAMs in situ (Copyright © 2024 American Chemical Society).

Figure 5

Schematic diagram of in vivo delivery process of framework swelling-triggered biodegradable CD@MSN and its application for photothermal imaging-guided tumor-targeted PTT cooperated with debris-mediated immunotherapy against tumor metastasis (Copyright © 2019 American Chemical Society).