<p>The current study presents the development of a Cetuximab (CTX)-functionalized chitosan–polydopamine (CS–PDA) hydrogel co-delivering calcium ions (Ca^{2 +}) and Gefitinib (GFT) for EGFR-targeted therapy against esophageal cancer through the induction of Ca²⁺ mediated cell death and potential immune modulatory effects. FTIR analysis confirmed the functional groups present in the fabricated hydrogel, while UV–Vis spectroscopy verified successful drug incorporation, and SEM analysis revealed a porous morphology suitable for efficient drug encapsulation. The hydrogel shows high drug loading efficiencies of 78.5 ± 2.3% for Ca^{2 +} and 81.6 ± 3.1% for GFT, with pH-responsive drug release reaching up to 70% under acidic conditions. NIR-activated CTX-CS-pDA@Ca^{2 +}/GFT hydrogel showed superior cytotoxicity in KYSE-140 cells, with significantly lower IC₅₀ values than free GFT. Further, JC-1 and AO/EB staining confirmed mitochondrial depolarization and apoptosis induction, while flow cytometry demonstrated that CTX-CS-pDA@Ca^{2 +}/GFT + NIR markedly induced apoptosis in KYSE-140 cells by combining EGFR inhibition, Ca^{2 +} -mediated stress, and NIR-enhanced ROS generation, resulting in reduced cell viability and increased apoptotic populations. Calcium imaging further validated intracellular Ca^{2 +} accumulation indicated enhanced Ca²⁺mediated cellular stress in treated cells. In vivo evaluation in a xenograft mouse model revealed tumor inhibition rates of 42%, 24%, 60%, 78%, and 92% for GFT, CS-pDA, CS-pDA@Ca^{2 +}/GFT, CTX-CS-pDA@Ca^{2 +}/GFT, and CTX-CS-pDA@Ca^{2 +}/GFT + NIR, respectively. The NIR-activated CTX-CS-pDA@Ca^{2 +}/GFT formulation achieved the most pronounced tumor regression with negligible impact on body weight, confirming its superior therapeutic efficacy and biosafety. Biochemical analyses of serum ALP, SGOT, urea, and creatinine levels confirmed the biocompatibility and safety of the fabricated hydrogel. Histopathological examination of excised tumor tissues supported the induction of apoptosis and tissue necrosis in treated groups. Furthermore, qRT-PCR and Western blot analyses demonstrated upregulation of Bax and cleaved caspase-3 and downregulation of Bcl-2 and EGFR/p-AKT signaling, supporting the dual mechanism of action. Besides, CTX-CS-pDA@Ca^{2 +}/GFT + NIR significantly upregulated pro-inflammatory cytokines (IL-6, TNF-α, and IFN-γ), indicating potential immunomodulatory activity associated with cytokine expression changes driven by targeted delivery, Ca^{2 +} -mediated stress, and NIR-triggered activation. Overall, this multifunctional hydrogel demonstrates strong potential as a localized and targeted therapeutic strategy for EGFR-overexpressing esophageal cancer through synergistic EGFR inhibition, Ca^{2 +} -mediated cytotoxicity, and potential immunomodulatory effects.</p>