Membrane and intracellular proteins represent the majority of validated cancer therapeutic targets, yet their subcellular localization-dependent functions and druggability remain incompletely understood, especially in the context of tumor-immune interactions. Membrane proteins such as immune checkpoint receptors, costimulatory molecules, and adhesion molecules orchestrate immune evasion or activation, serving as primary targets for monoclonal antibodies and CAR-T cell therapies. Intracellular proteins, especially signaling kinases and transcription factors, regulate immune cell polarization and tumor microenvironment (TME) remodeling but are notoriously challenging to target due to subcellular inaccessibility. Recent breakthroughs in proteomics and spatial biology have revealed that protein targets within membrane microdomains, organelles, or nuclear compartments dictate their interactions with immune effectors. Structural and functional studies further demonstrate how subcellular context shapes the efficacy of immunotherapies, including CAR-T cells and checkpoint inhibitors. However, gaps persist in translating these mechanisms into therapies that overcome TME-mediated immune exclusion, particularly for "undruggable" intracellular drivers of immunosuppression. Integrating immunology, immune profiling, and target-specific drug delivery is critical to unlocking synergies between cancer cell-targeted agents and immune modulators.

This Research Topic aims to bridge the mechanistic understanding of membrane and intracellular protein targets with innovative drug discovery and translational strategies. By integrating cell biology, structural biology, and medicinal chemistry, we seek to showcase studies that address immune evasion mechanisms driven by protein dynamics, decode protein localization-dependent functions, develop targeted therapies (small molecules, biologics, nanomedicines), and address unmet clinical needs in cancer treatment, with a focus on translating basic science into actionable interventions.

We welcome Original Research, Review, Mini Review, and Perspective articles on themes including, but not limited to:

1) Mechanisms of tumor-immune crosstalk: membrane protein-mediated immune evasion, intracellular regulation of immune cell fate, reprogramming, or heterogeneity of the tumor microenvironment affected by protein targets.

2) Structural and functional characterization of membrane or intracellular signaling hubs, with a focus on how subcellular localization influences protein conformation, interaction networks, and immunomodulatory functions.

3) Targeted therapy development for membrane and intracellular proteins: Preclinical/clinical studies exploring small molecules, biologics, or nanomedicines designed to disrupt immunosuppressive interactions or enhance immune cell trafficking.

4) Technological and computational innovations for subcellular target discovery: Omics approaches to map key protein targets in tumor-immune niches; machine learning and molecular modeling to predict drug-target interactions and optimize therapeutic specificity.

5) Combination strategies and resistance mechanisms: Mechanistic studies on synergies between immunotherapies and protein-targeted therapies, with a focus on overcoming adaptive resistance.

6) Translational biomarkers and diagnostic tools: Development of molecular signatures to predict treatment response, or monitor immune dynamics based on protein targets.

Submissions should emphasize functional validation of molecular targets, interdisciplinary methodologies, and clear links between basic science and clinical application, welcoming contributions from immunology, oncology, bioengineering, and precision medicine.

Are you interested in contributing a manuscript to this Research Topic?

Deciphering Membrane and Intracellular Protein Targets in Cancer: Subcellular Mechanisms, Drug Discovery, and Translational Interventions