Introduction: Cancer treatment has evolved with the development of targeted therapies and immunotherapies, providing precision strategies that improve survival and quality of life. Targeted therapies interfere with specific molecular pathways essential for tumor growth, while immunotherapies enhance the host immune system’s ability to recognize and destroy cancer cells. Despite their success, monotherapy often results in incomplete responses or acquired resistance. Combining these modalities has emerged as a promising approach to synergistically enhance anti-tumor effects, reduce resistance, and broaden patient eligibility. Understanding the mechanisms, potential benefits, and limitations of combination therapy is crucial for clinical application. This review explores the current landscape, clinical outcomes, and challenges of combining targeted therapy with immunotherapy in cancer.
Methods: The review aims to evaluate the scientific rationale, clinical outcomes, and challenges of combining targeted therapy with immunotherapy. Specific questions include:
*How do targeted therapies and immunotherapies interact at the molecular and cellular level?
*What are the clinical outcomes of combination regimens across different cancer types?
*What strategies optimize efficacy while minimizing adverse effects?
A structured narrative review was performed. Literature from PubMed, Scopus, and Web of Science (2015–2025) was searched using keywords: “targeted therapy,” “immunotherapy,” “combination therapy,” and “cancer resistance.” Inclusion criteria included peer-reviewed original research and reviews reporting molecular mechanisms, preclinical studies, and clinical outcomes of combination strategies. Exclusion criteria comprised case reports, editorials, and unrelated studies. Data extraction focused on cancer type, combination regimen, treatment outcomes, toxicity, and biomarker-guided patient selection. Studies were categorized into (1) mechanisms of synergy, (2) preclinical evidence, and (3) clinical applications. Quality assessment emphasized methodological rigor, reproducibility, and relevance to clinical oncology.
Results: Mechanisms of synergy: Targeted therapies can modulate tumor microenvironment, enhancing immune cell infiltration and antigen presentation. Immunotherapy, in turn, can potentiate targeted therapy efficacy by promoting T-cell-mediated cytotoxicity.
Preclinical evidence: Studies in melanoma, non-small cell lung cancer, and breast cancer demonstrate enhanced tumor regression and reduced resistance when therapies are combined. Preclinical models reveal that sequencing and dosing are critical to maximize synergy.
Clinical applications: Combination regimens, such as BRAF/MEK inhibitors with PD-1 blockade, show improved response rates and progression-free survival. However, immune-related adverse events, overlapping toxicities, and heterogeneity in patient response present challenges. Biomarker-guided approaches, including PD-L1 expression and mutational burden, help optimize patient selection and predict response.
Overall, combining targeted therapy with immunotherapy represents a promising strategy to overcome monotherapy limitations, though further studies are needed to refine protocols and improve safety profiles.
Conclusion: Combination therapy offers the potential to enhance anti-tumor efficacy, reduce therapeutic resistance, and expand clinical benefit to diverse patient populations. Mechanistic insights reveal that targeted therapy can remodel the tumor microenvironment, making it more susceptible to immune attack. Challenges include managing overlapping toxicities, immune-related adverse events, and identifying optimal sequencing and dosing. Future research should prioritize mechanistic studies, predictive biomarkers, and personalized treatment regimens. Integration of multi-omics and longitudinal monitoring can improve treatment outcomes and safety.
Combining targeted therapy with immunotherapy holds promise for enhancing efficacy, overcoming resistance, and broadening therapeutic options in cancer. Optimizing patient selection, dosing, and sequencing is crucial to maximize benefits while minimizing adverse effects. Continued preclinical and clinical studies are necessary to establish best practices and personalized combinatorial strategies. This approach represents a step toward precision oncology and improved patient outcomes.