Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options, and the integration of immune checkpoint inhibitors (ICIs) into treatment regimens has reshaped the therapeutic landscape. However, challenges such as rapid resistance and lack of effective predictive biomarkers remain. This review highlights the pivotal roles of biomarkers in SCLC, underscoring their contributions to treatment resistance across tumor-intrinsic mechanisms, immune landscape of the tumor microenvironment (TME) and systemic host factors. Tumor-intrinsic features, including molecular subtypes, genetic alterations such as TP53 and RB1 mutations, and tumor mutation burden (TMB), have shown varying associations with ICI efficacy. Notably, the SCLC-I (inflamed) molecular subtype appears more responsive to immunotherapy. Within the TME, programmed cell death ligand 1 expression, tumor-infiltrating lymphocytes (TILs), regulatory T cells, myeloid-derived suppressor cells, and tissue-associated cytokines and chemokines contribute to immune modulation. High CD8+ TILs are linked to better outcomes, while increased immunosuppressive populations often suppress anti-tumor response. Systemic factors, encompassing both tumor-derived (ctDNA, CTCs, tumor-derived EVs) and host-derived (circulating immune cell phenotypes, MHC expression, immune profile, baseline clinical characteristics) components, provide valuable insights into treatment response and prognosis. Further research is needed to validate biomarkers and investigate combination approaches to overcome resistance, offering hope for improved patient outcomes in SCLC.
Shuxing Wang, Xinrui Zhao, Yue-yue Zeng et al.· Critical reviews in oncology...· 0 citations
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central sensor of innate immunity that plays critical roles in recognizing cytosolic DNA and initiating antitumor immune responses. However, this pathway exhibits extensive spatiotemporal duality and context dependency in tumor regulation. In recent years, modulating this pathway to convert immunologically "cold" tumors into immunologically "hot," inflamed tumors has emerged as a cutting-edge strategy to reverse resistance to immune checkpoint inhibitors (ICIs). This review outlines the molecular mechanisms underlying the activation and regulation of the cGAS-STING pathway, with emphasis on its complex role in orchestrating the tumor immune phenotypic switch. A nuanced analysis of the pathway's duality distinguishes between acute immunostimulatory activation and chronic, pro-tumorigenic inflammation driven by chromosomal instability (CIN). Furthermore, current evidence regarding direct and indirect T-cell modulation, as well as pathway-mediated remodeling of the tumor microenvironment (TME) across diverse malignancies, is discussed in detail. Crucially, the current bottlenecks in clinical translation are described, including evaluation of the failure of first-generation agonists and the promise of next-generation delivery platforms such as antibody-drug conjugates (ADCs) and nanoparticle systems. Finally, a novel strategic framework is proposed involving mapping of specific STING-targeted modalities to distinct TME phenotypes, such as immune-desert, immune-excluded, and exhausted-inflamed states. A detailed understanding of the cGAS-STING axis has substantial value in providing theoretical guidance and supporting clinical translation in the development of next-generation combination immunotherapies, as well as broadening the patient population benefiting from clinical interventions.
Xinrui Zhao, Shuai Meng, Hanzeng Cheng et al.· Cancer Biology and Medicine· 0 citations
