Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy characterized by a complex tumor microenvironment (TME) that plays a critical role in disease progression and therapeutic resistance. Tumor-infiltrating immune cells, including T lymphocytes, macrophages, dendritic cells, and myeloid-derived suppressor cells, exhibit dual functions, either promoting or suppressing tumor growth depending on their phenotype and interactions within the TME. The presence of immune evasion mechanisms, such as the loss of human leukocyte antigen (HLA) expression, upregulation of immune checkpoint molecules, and metabolic reprogramming (hypoxia-induced glycolysis and lactate accumulation), further contributes to immune suppression and poor treatment responses. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent/metastatic HNSCC, response rates remain highly variable, underscoring the need for biomarker-driven patient selection and combinatorial therapeutic strategies. This review provides a comprehensive analysis of the role of immune cells in the TME of HNSCC, discusses the mechanisms underlying immune escape, and explores emerging immunotherapeutic and epigenetic-targeting approaches aimed at enhancing antitumor immune responses and improving clinical outcomes.

Hypoxia is a hallmark of solid tumors, driving metabolic reprogramming and immune evasion. In lung cancer, hypoxia-induced activation of carbonic anhydrase IX (CAIX) promotes lactate accumulation and extracellular acidification, fostering an immunosuppressive tumor microenvironment (TME). Analysis of public datasets revealed that patients with high CAIX expression exhibited significantly reduced median survival (p < 0.001). Moreover, CAIX correlated with HIF-1α, PD-L1, and immunosuppressant molecules, linking hypoxia-driven metabolic alterations with immune dysfunction. Here, we evaluated the capacity of 4-methylumbelliferone (4Mu) to counteract these effects and enhance antitumor immunity. In vitro, hypoxia increased CAIX and monocarboxylate transporter -4 (MCT4) expression in lung carcinoma cells, elevated lactate release, and reduced extracellular pH while promoting an M2-like macrophage profile and impairing antigen-specific splenocyte proliferation (p < 0.01). Treatment with 4Mu downregulated CAIX expression, restored extracellular pH, decreased lactate secretion, and rescued lymphocyte proliferation (p < 0.01). In vivo, 4Mu reduced CAIX expression, shifted macrophage polarization toward a pro-inflammatory phenotype, and enhanced CD8+ T cell infiltration. 4Mu was safe and well tolerated, and notably, combined with anti-PD-1 therapy, it synergistically inhibited tumor growth and increased both CD4+ and CD8+ T cell infiltration. These findings support 4Mu as a metabolic modulator capable of mitigating CAIX-driven acidosis and improving the efficacy of immunotherapy in lung cancer.

Los inhibidores de tirosina quinasa (TKI) han revolucionado el tratamiento del cáncer de pulmón de células no pequeñas (CPCNP) con alteraciones genéticas específicas, como la translocación de ALK. Sin embargo, su impacto en el sistema inmunológico y su asociación con infecciones oportunistas, como la tuberculosis (TB), sigue siendo poco explorado. Caso clínico: Varón de 53 años con CPCNP ALK-positivo, estadio IV por compromiso pleural, inició tratamiento con brigatinib, mostrando respuesta parcial a los 3 meses. Al quinto mes, presentó fiebre persistente, linfopenia grado 1 y derrame pleural derecho. Los estudios histopatológicos revelaron pleuritis granulomatosa necrotizante compatible con TB, a pesar de ausencia de antecedentes tuberculosos. Los cultivos y tinciones para micobacterias fueron negativos, pero se inició tratamiento antituberculoso empírico con esquema de 4 drogas. Brigatinib fue reemplazado por alectinib para evitar hepatotoxicidad por los antifímicos. El paciente mostró mejoría clínico-radiológica de la TB. Este reporte subraya la necesidad de vigilancia activa para infecciones oportunistas en pacientes tratados con TKI, incluso en ausencia de inmunosupresión tradicional. Se recomienda evaluación de TB latente previa al tratamiento en áreas endémicas y monitorización estrecha de síntomas sugestivos. Futuros estudios deben clarificar el riesgo real y estrategias profilácticas en este contexto.

Non–small cell lung cancer (NSCLC) represents a critical public health crisis in Latin America (LA), the leading cause of cancer-associated mortality across the region. Although global incidence rates are shifting, the burden in low- and middle-income countries is projected to increase significantly by 2030. Beyond the impact of tobacco, LA faces unique challenges derived from environmental exposures and diverse genetic ancestry that shape a molecular landscape distinct from other regions. This has resulted in a high prevalence of actionable drivers, particularly EGFR mutations, positioning a large segment of the population as ideal candidates for precision medicine approaches. However, current efforts to address this epidemic fall short of regional needs, as the potential of precision oncology remains largely unrealized due to multilevel systemic and economic barriers. Despite the scientific potential of targeted therapies to drastically improve survival, LA has not broadly or expeditiously adopted these strategies. A profound implementation gap is characterized by a reliance on inefficient single-gene testing, fragmented regulatory frameworks, and severe infrastructural limitations. Consequently, only a minimal proportion of the regional patient population benefits from recent advances, whereas the majority continue to receive empirical chemotherapy with significantly inferior survival outcomes. Addressing these disparities requires a steadfast focus on systemic transformation, ranging from establishing centralized genomic hubs to implementing structured educational programs. Standardizing care through molecular tumor boards (MTBs) and harmonizing regulatory pathways are essential steps in translating research into clinical benefits. In this review, we discuss the unique molecular epidemiology of the region and the challenges of treatment implementation, focusing on the urgent need to integrate new technologies to ensure equitable access to precision oncology. LA has one of the highest potential population-level benefits from precision oncology in NSCLC; however, systemic barriers prevent this molecular opportunity from translating into equitable survival gains (Graphical abstract).