Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and B7/CTLA-4 pathways, has revolutionized cancer treatment by harnessing the immune system to recognize and eradicate tumors. While these therapies have shown remarkable success across various malignancies, resistance remains a significant challenge. Many patients either fail to respond to ICIs (primary resistance) or eventually develop resistance after an initial period of clinical benefits (acquired resistance). This resistance is driven by multifaceted mechanisms, including tumor-intrinsic factors, the modifications within the tumor microenvironment, and diverse immune evasion strategies. As a result, there is an urgent need to investigate novel therapeutic avenues to overcome these resistance mechanisms and extend the benefits of immunotherapy to a broader patient population.

The goal of this research topic is to provide a comprehensive and in-depth exploration of the molecular and cellular mechanisms driving resistance to cancer immunotherapy. By assembling cutting-edge research and expert reviews, this collection aims to deepen our understanding of how immune evasion, tumor microenvironment dynamics, and intrinsic tumor cell adaptations contribute to resistance. The overarching objective is to identify novel therapeutic strategies and biomarkers that can overcome these resistance mechanisms, thereby improving the efficacy of immunotherapy in treatment-refractory cancers. This research topic aims to foster interdisciplinary collaboration and innovation, ultimately advancing personalized immunotherapy approaches and enhancing clinical outcomes for patients with resistant lung, breast, and other challenging cancer types.

The aim of this Research Topic is to offer a comprehensive update on the molecular and cellular mechanisms underlying resistance to cancer immunotherapy. The focus is on understanding how immune evasion, changes in the tumor microenvironment, and intrinsic adaptations of tumor cells contribute to resistance. We welcome submissions of original research, review articles, mini-reviews, opinions, and perspectives that address these key aspects of resistance. This special theme collection includes, but is not limited to, the following sub-topics:

(1) Molecular Mechanisms Underlying Immune Checkpoint Inhibitor Resistance
(2) Tumor Microenvironment Dynamics, including cellular composition and spatial relationship, in Immunotherapy-Resistant Lung and Breast Cancers
(3) The Role of Immune Evasion in Resistance to Cancer Immunotherapy
(4) Advances in Combination Therapeutic Strategies to Overcome Immunotherapy Resistance
(5) Novel Immune Checkpoint Inhibitors Beyond PD-1/PD-L1 and B7/CTLA-4 pathway, including TIGIT, LAG3, TIM3, IDO, and so on.
(6) Targeting Tumor-Associated Macrophages, Myeloid-Derived Suppressor Cells, and Other Myeloid Cells in Immunotherapy-Resistant Cancers
(7) The Impact of Intra-Tumoral Heterogeneity on Immunotherapy Efficacy
(8) Epigenetic Modulation of Immune Responses in Immunotherapy-Resistant Cancers
(9) Biomarkers for Predicting and Monitoring Resistance to Immunotherapy
(10) Personalized Immunotherapeutic Approaches for Immunotherapy-Resistant Cancers
(11) Integration of Targeted Therapies and Immunotherapy in Immunotherapy-Resistant Tumors
(12) Overcoming Immunotherapy Resistance through Modulation of the Tumor Microbiome
(13) Immune Modulation Strategies to Enhance the Efficacy of Immune Checkpoint Inhibitors
(14) Role of Non-coding RNAs in Mediating Resistance to Immunotherapy
(15) Preclinical Models for Investigating Mechanisms of Immunotherapy Resistance in Cancer
Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal.

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Breaking Barriers: New Frontiers in Immunotherapy for Resistant Cancers