The　efficacy　of　neoantigen-reactive　T　cells　(NRT)　therapy　in　solid　tumors,　encompassing　aspects　such　as　infiltration,　recognition,　cytotoxicity,　and　enduring　persistence,　is　notably　influenced　by　the　immunological　microenvironment.　This　study　endeavors　to　investigate　whether　the　co-administration　of　pemetrexed　and　cisplatin　augments　the　therapeutic　efficacy　of　NRT　therapy　in　lung　cancer.　Neoantigens　were　predicted　using　a　comprehensive　analysis　of　mutation　data　from　Lewis　lung　carcinoma　cells　and　mouse　tail　tissues.　The　immunogenicity　of　NRT　cells　was　assessed　through　flow　cytometry　and　IFN-gamma　ELISpot　assays.　A　mouse　model　of　NSCLC　was　used　to　investigate　the　anti-tumor　effects　of　NRT　combined　with　chemotherapy.　The　combination　of　NRT　cells　and　chemotherapy　significantly　inhibited　tumor　growth　in　a　mouse　model,　increased　CD3+/CD137+　T　cells　to　promote　IFN-gamma　secretion　from　NRT　cells,　and　up-regulated　the　levels　of　inflammatory　cytokine　proteins　including　IFN-gamma,　TNF,　IL-6　and　IL-10.　Immunofluorescence　analysis　confirmed　increased　T-cell　infiltration　in　tumor　tissues　without　adverse　effects　on　vital　organs.　In　addition,　transcriptome　analyses　indicated　that　the　tumor　microenvironment　was　altered　to　favor　M1-like　macrophages　with　an　increased　M1/M2　ratio,　creating　a　pro-inflammatory　environment.　The　integration　of　NRT　with　frontline　chemotherapy　for　lung　cancer　could　yield　profoundly　ideal　therapeutic　outcomes.