Natural and Peptide-Inspired Anticancer Strategies in Lung Cancer: A Structured Systematic Review and Qualitative Synthesis of in vivo Therapeutic Platforms

Abstract

Context: Lung cancer remains one of the leading causes of cancer-related mortality worldwide, largely attributable to the limited selectivity and cumulative toxicity of conventional anticancer therapies. Despite advances in chemotherapy and targeted agents, treatment-associated adverse effects and therapeutic resistance continue to hinder clinical outcomes. In this context, natural and naturally derived peptides have emerged as promising anticancer candidates due to their inherent biocompatibility, structural diversity, and capacity to selectively target cancer-associated molecular and cellular pathways. Objectives: A comprehensive evaluation of in vivo evidence is essential to clarify their therapeutic potential and mechanistic relevance in lung cancer. Data Sources: A structured systematic literature search was conducted exclusively in the PubMed database to identify original in vivo studies published between 2015 and 2025. Study Selection: Eligible studies were selected using predefined inclusion criteria emphasizing lung cancer animal models and peptide-based interventions derived from natural sources/natural scaffolds or operationally defined peptide-inspired designs. Studies limited to in vitro experiments, review articles, duplicates, and publications lacking quantifiable antitumor outcomes were excluded. Reporting followed PRISMA 2020, and 29 eligible in vivo studies were included in a qualitative synthesis. Data Extraction: Because the search was restricted to a single database, studies indexed exclusively in Embase, Scopus, or Web of Science may have been missed, and findings should be interpreted as a structured qualitative synthesis rather than an exhaustive evidence capture. Results: Analysis of eligible in vivo studies indicates that natural, naturally derived, and peptide-inspired strategies can inhibit lung tumor growth through convergent biological mechanisms. For synthesis, studies were grouped into four principal mechanistic clusters based on the primary mechanism most directly linked to in vivo outcomes: (1) inhibition of oncogenic kinases and dysregulated signaling pathways; (2) modulation of NF-κB-associated inflammatory responses; (3) induction of mitochondrial and lysosomal dysfunction culminating in tumor cell death; and (4) suppression of angiogenesis and metastatic progression. Multi-modal peptides were discussed as such, but were not double-counted across clusters. Several platforms also incorporated rational optimization to improve stability, tumor targeting, and delivery efficiency. Conclusions: The in vivo literature supports natural, naturally derived, and peptide-inspired approaches as experimental preclinical platforms with antitumor activity in lung cancer models. However, the evidence base is dominated by immunocompromised xenograft studies, pharmacokinetic and safety reporting is inconsistent, chronic toxicity and immunogenicity are rarely evaluated, and none of the peptides discussed have entered lung cancer clinical trials. Accordingly, these findings should be viewed as proof-of-concept platforms requiring extensive translational validation in clinically relevant models before inferences about clinical viability can be made.