Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges

Abstract

Resistance to targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) is a significant challenge in the treatment of this disease. The mechanisms of resistance are multifactorial and include molecular target alterations and activation of alternative pathways, tumor heterogeneity and tumor microenvironment change, immune evasion, and immunosuppression. Promising strategies for overcoming resistance include the development of combination therapies, understanding the resistance mechanisms to better use novel drug targets, the identification of biomarkers, the modulation of the tumor microenvironment and so on. Ongoing research into the mechanisms of resistance and the development of new therapeutic approaches hold great promise for improving outcomes for patients with NSCLC. Here, we summarize diverse mechanisms driving resistance to targeted therapy and immunotherapy in NSCLC and the latest potential and promising strategies to overcome the resistance to help patients who suffer from NSCLC.

Keywords: immunotherapy; mechanisms of drug resistance; non-small cell lung cancer; promising strategies; targeted therapy.

Figure 1

Targeted therapy resistance in NSCLC. The image shows the mechanisms of the main targets that generate resistance in targeted therapy for NSCLC. The above eight targets generate drug resistance through gene mutation(mut), activation(act), amplification(amp), or fusion(fus). Mutated targets have been marked in black. In particular, mutations in PTEN, an inhibitor of PI3K, also lead to tumor progression. Created with BioRender.com.

Figure 2

Immunotherapeutic resistance in NSCLC. The image shows the mechanisms that generate resistance in immunotherapy for NSCLC. It can be classified into two parts: immune system and tumor microenvironment (TME), the latter can be further divided into endogenous and exogenous. In immune system, impaired antigen presentation leads to the failure to activate normal immune responses such as T cell priming, activation, trafficking, and migration. In addition, endogenous alterations in the tumor microenvironment leads to the development of drug resistance, including gene overexpression and gene mutation. The former includes T cell co-inhibitory receptors on immunosuppressive cells, and the latter includes genes involved in IFqN-γ response, antigen presentation pathways, and immunoregulation. Exogenous factors such as dynamic interactions within the TME lead to increased infiltration of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, M2 macrophages, and tumor-associated macrophages. Created with BioRender.com.